bp(GO:autophagy)
Another modulator of A-LS implicated in AD pathology is transcription factor EB (TFEB), a master regulator of lysosome biogenesis PubMed:29758300
A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146). PubMed:25784053
Neuronal autophagy has been found to occur following chronic, low-grade proteasomal inhibition in cultured neuroblastoma cells (Ding et al., 2003) and may reflect activation of the lysosomal system as cells try to protect themselves during stress (Larsen and Sulzer, 2002). PubMed:14556719
Reduced levels of lipofuscin, LC3, and p62 have been observed in motor neurons of SOD1(G85R) mice (92). Treatment with the autophagy inhibitor chloroquine restored lipofuscin, LC3, and p62 levels in motor neurons, suggesting that mutant SOD1 causes hyperactive autophagy in mice (92). PubMed:25784053
An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145). PubMed:25784053
An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145). PubMed:25784053
An in silico screen based on the structure of 10-NCP, an Akt inhibitor that potently induces autophagy (144), identified the molecules FPZ and MTM as potent activators of autophagic flux and clearance of TDP-43 in mammalian cells (145). PubMed:25784053
A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146). PubMed:25784053
A screen for autophagy inducers in yeast identified the molecules SMER-10, -18, and -28 as TOR-independent activators of autophagy (146). PubMed:25784053
In contrast, α-synuclein overexpression impairs autophagy in mammalian cells and mice through reduced expression of RAB1A, thereby inhibiting autophagosome formation (88). PubMed:25784053
Reduced levels of lipofuscin, LC3, and p62 have been observed in motor neurons of SOD1(G85R) mice (92). Treatment with the autophagy inhibitor chloroquine restored lipofuscin, LC3, and p62 levels in motor neurons, suggesting that mutant SOD1 causes hyperactive autophagy in mice (92). PubMed:25784053
In contrast to findings in HD, AD, and PD, a recent study has suggested that autophagy is enhanced in ALS mice. PubMed:25784053
For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008). PubMed:23528736
This mechanism may be involved in its promotion of autophagy, reduction in cel- lular levels of α-synuclein, SOD1, Htt and tau 126 , ame- lioration of motor function in a P301L mouse model of tauopathy 127 and slowing of disease progression in SOD1 mice 128 . PubMed:30116051
For example, methylene blue coun- ters tau oligomerization and promotes autophagy 101,102 (Supplementary Table 4). PubMed:30116051
Other compounds that act through AMPK acti- vation include the antiaggregant methylene blue (Supplementary Box 1), which elevated levels of beclin 1, p62 and LC3, induced autophagy and suppressed tau in organotypic neuronal cultures and a mouse model of FTD 101,102 . PubMed:30116051
Calpeptin, a cell-permeable calpain inhibitor, can also reduce Htt proteinopathy via induction of autophagy 103,105 . PubMed:30116051
Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 . PubMed:30116051
In addition, calcitriol (the active metabolite of vitamin D 3 ) elicited AMPK-dependent autophagy in a neurochemical lesion-induced model of PD 129. PubMed:30116051
Indeed, clonidine and rilmenidine, two G i /G o -coupled α 2 -adrenergic receptor and imidazoline 1 receptor agonists, stimulate autophagy and cleared Htt in cellular 103 and animal models of HD 104 . PubMed:30116051
The antidiabetic drug metformin, a prototypical activator of AMPK, induced autophagy and increased longevity in mice 116 . PubMed:30116051
For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008). PubMed:23528736
Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 . PubMed:30116051
Enhancing auto- phagy with rapamycin reduced levels of α-synuclein, FUS and Htt 130–132 . PubMed:30116051
Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 . PubMed:30116051
The aminoimidazole derivative 5-aminoimidazole- 4-carboxamide ribonucleotide (AICAR) undergoes intra- cellular transformation to an AMP analogue that triggers AMPK-mediated autophagy 21,108 . PubMed:30116051
The di-glucose derivative trehalose inhibits the sol- ute carrier 2A (SLC2A) family of glucose transporters to promote AMPK-induced autophagy and reduce neurotoxic protein load, although it also exerts other actions downstream in the ALN 4,120 . PubMed:30116051
Mutations in C9ORF72 (the most prevalent risk gene for familial ALS and FTD) are likewise linked to disruption of the ALN, including interference with dynactin–dynein coordinated transport of autophagosomes along axons of motor neurons to the perikarya 82,88 . PubMed:30116051
Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 . PubMed:30116051
Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 . PubMed:30116051
Genetic knockdown of calpain 1 or calpain 2 or overexpression of their endogenous inhibitor, calpastatin, increased autophagy and cleared aggregates in SK-N-SH cells overexpressing a mutant form of Htt 103 . PubMed:30116051
Fourth, homozygous mutations of lyso- somal β-glucocerebrosidase (βGCase; also known as GBA) provoke the LSD Gaucher disease, which is linked to decreased ALN flux, α-synuclein accumulation and a fivefold increase in risk of PD 43 (Supplementary Box 1). PubMed:30116051
Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 . PubMed:30116051
Some of these lead to an impairment of the ALN owing to reduced activation of beclin 1; another repercussion may be altered process- ing of APP, providing an unexpected link to AD 69,71–73 . PubMed:30116051
PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553
PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553
For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008). PubMed:23528736
and lithium (Shimada et al., 2012) in human tau over-expressing Tg mice induced autophagy, which is accompanied by the reduced levels of pathological tau and NFT formation in tauopathy model mice. PubMed:23528736
Trehalose, an natural disaccharide and mTOR-independent activator of autophagy (Sarkar et al., 2007), showed an effect on neuronal survival, reducing the level of tau aggregates in the brain of human tauopathy model mice (Kruger et al., 2011; Rodriguez-Navarro et al., 2010; Schaeffer et al., 2012). PubMed:23528736
Methylene blue, which has been known to directly inhibit tau aggregation, is also capable to induce autophagy and reduce total and phospho-tau levels with improved cognitive performance in tau transgenic mice by oral administration (Congdon et al., 2012). PubMed:23528736
Oxidative stress also upregulates autophagy induction, which limits the production of reactive oxygen species from dysfunctional mitochondria. PubMed:23528736
Aging, a major risk factor for AD, affects both the UPS and autophagy. PubMed:23528736
The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736
The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736
The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation. PubMed:23528736
Importantly, the Hsps are also critical at the end of a protein’s life, as they facilitate turnover by the proteasome system and the clearance of proteotoxic aggregates by autophagy [53] PubMed:21882945
During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy PubMed:21882945
During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy PubMed:21882945
During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy PubMed:21882945
An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493
Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012) PubMed:29626319
Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319
Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012) PubMed:29626319
Recent acknowledged drugs can improve autophagy by acting on the process of autophagy-lysosome formation and then increasing tau clearance, such as methylene blue, lithium, and trehalose (Congdon et al. 2012; Kruger et al. 2012; Shimada et al. 2012) PubMed:29626319
Proteasome inhibitors and trehalose increase autophagy and decrease tau content by up-regulating the expression of cochaperone BAG3 targeting tau to the autophagy pathway for degradation (Lei et al. 2015) PubMed:29626319
Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319
Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319
Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319
Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319
Protein phosphatase 2A agonists are reported to activate autophagy by affecting AMPK and mTORC1 signaling pathways (Magnaudeix et al. 2013) PubMed:29626319
For example, like Aβ, clearance of pTau/NFT also can be regulated by TFEB, which increases the activity of autophagy and lysosome (Polito et al. 2014) PubMed:29626319
Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011). PubMed:22020111
SQSTM1, induced 20-fold, encodes sequestosome-1, a participant in the autophagy pathway recently shown to be necessary to avoid premature senescence in human fibroblasts (Kang et al., 2011). PubMed:22020111
In addition to the direct modulation of protein generation, lipids can also influence the levels of proteins through autophagic clearance; for instance, increasing lipid contents has been shown to impair autophagy [72]. PubMed:29758300
For instance, rapamycin, an inhibitor of the Ser/Thr protein kinase mammalian target of rapamycin (mTOR), improves cognitive function and reduces Aβ in AD mouse model by enhancing autophagic flux [23]. PubMed:29758300
Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300
Even early autophagic activation may become impaired due to progressively diminishing lysosomal clearance of substrates. PubMed:29758300
TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300
Suppression of BIN1 disrupts cellular trafficking of BACE1 and reduces BACE1 lysosomal degradation, leading to increased Aβ production [103]. PubMed:29758300
Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300
A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300
Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53] PubMed:29758300
PSEN1 M146L and A246E mutant cortical neurons have been shown to possess decreased activation of the CLEAR (coordinated lysosomal expression and regulation) gene network, as measured by a TFEB-driven luciferase assay, consistent with a reduction in autophagic activity [131]. PubMed:29758300
PSEN1 M146L and A246E mutant cortical neurons have been shown to possess decreased activation of the CLEAR (coordinated lysosomal expression and regulation) gene network, as measured by a TFEB-driven luciferase assay, consistent with a reduction in autophagic activity [131]. PubMed:29758300
Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300
Chronic low-level stimulation of autophagy through peripheral administration of rapamycin or other agents (Tian et al. 2011), or enhancing lysosomal proteolysis selectively (Sun et al. 2008; Yang et al. 2011), can markedly diminish Ab levels and amyloid load in APP transgenic mice, underscoring the importance of lysosomal clearance of Ab. PubMed:22908190
Consistent with these findings, rapamycin induction of autophagy reduces tau pathology in the triple transgenic AD-mouse model (Caccamo et al. 2010), whereas in other models, autophagic–lysosomal dysfunction amplifies tau pathology and tau neurotoxicity (Hamano et al. 2008; Khurana et al. 2010). PubMed:22908190
Similar autophagy pathology is observed when lysosomal proteolysis is inhibited (Ivy et al. 1984; Koike et al. 2005; Yang et al. 2008). PubMed:22908190
Interdependence of the proteasome and lysosomal system is also suggested by observations that, when proteasome activity is inhibited, proteins accumulate that become substrates for autophagy (Fortun et al. 2003) PubMed:22908190
Autophagy may also modulate synaptic plasticity, which involves structural remodeling of nerve terminals (Boland et al. 2006) and the trafficking and degradation of receptors and other synaptic proteins (Leil et al. 2004; Rowland et al. 2006). PubMed:22908190
For example, p62, an adaptor protein for autophagy, also influences proteasomal degradation, whereas VCP/p97 acting through p62 and ubiquitin regulates both the proteasome-dependent endoplasmic reticulum–associated degradation (ERAD) pathway and aspects of autophagosome maturation (Tresse et al. 2010). PubMed:22908190
Induction of autophagy is generally controlled by the mTOR kinase (mammalian Target of Rapamycin), which is regulated by growth factors (especially insulin) and nutrient levels. PubMed:22908190
Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD PubMed:22908190
For example, immunocytochemistry showing the presence of K63- linked polyubiquitin in a fraction of the NFTs in AD cortex (Paine et al. 2009) suggests an active involvement of autophagy in the mechanism of AD. PubMed:22908190
Specifically, it is suggested that K63-linked polyubiquitin chains recruit p62 and HDAC6 providing a signal for autophagic degradation [92,93]. PubMed:18930136
In addition, inducing autophagy in an TOR-independent manner using lithium [53] or trehalose [54–56] has been shown to accelerate clearance of disease proteins in vitro [56] and protect against neurodegeneration in mouse and Drosophila models of Huntington’s disease [53,54]. PubMed:18930136
In addition, inducing autophagy in an TOR-independent manner using lithium [53] or trehalose [54–56] has been shown to accelerate clearance of disease proteins in vitro [56] and protect against neurodegeneration in mouse and Drosophila models of Huntington’s disease [53,54]. PubMed:18930136
Pharmacological upregulation of autophagy can be accomplished using the drug rapamycin, which works by inhibiting TOR (target of rapamycin), a pleiotropic molecule that negatively regulates autophagy, among other functions PubMed:18930136
The initial step in autophagy involves expansion of a membranous structure called the “isolation membrane” or “phagophore” that engulfs a portion of the cell; the membrane eventually fuses to form a new double-membraned structure known as an autophagosome (Figure 1). PubMed:18930136
Recent advances have demonstrated that autophagy also serves a surprisingly diverse array of additional functions, including organelle clearance, antigen presentation, elimination of microbes, as well as regulation of development and cell death [9]. PubMed:18930136
Several lines of evidence suggest that there is an impairment of autophagy resulting from impaired autophagosome-lysosome fusion combined with decreasing efficiency of the lysosomal system [60]. PubMed:18930136
In addition to aggresome formation, impairment of the UPS in vitro has been found to induce autophagy [63,64]. PubMed:18930136
The process of autophagy is controlled by parallel activation cascades that involve ubiquitin-like (UBL) protein modification, strikingly similar to the activation cascade that regulates the UPS (Figure 2a). PubMed:18930136
Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136
Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation PubMed:18930136
Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology. PubMed:18930136
Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation PubMed:18930136
Thus, it has been suggested that p62 provides a key link between autophagy and the UPS by facilitating autophagic degradation of ubiquitinated proteins. PubMed:18930136
Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology. PubMed:18930136
This model is consistent with an older study showing that inactivation of the ubiquitin-activating enzyme E1 leads to a defect in autolysosomal degradation and to an absence of ubiquitin-positive proteins within lysosomes [68]. PubMed:18930136
Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation PubMed:18930136
For example, in a Drosophila model of X-linked spinobulbar muscular atrophy (SBMA), a polyglutamine disease, degeneration was strongly enhanced by genetic inhibition of autophagy [50]. PubMed:18930136
It has also been suggested that autophagy plays a role in the initiation or progression of some neurodegenerative diseases [20]. PubMed:18930136
Insight into the role of autophagy in neurodegeneration has been provided by studies indicating that: 1) some neurodegenerative disease-related proteins are degraded by autophagy, 2) impairment of autophagy promotes neurodegeneration in animal models and several human neurodegenerative diseases, and 3) manipulation of autophagy modifies phenotypes in animal models of neurodegeneration. PubMed:18930136
Specifically, ROS have been shown to regulate a wide variety of signalling pathways including anti- inflammatory responses and adaptation to hypoxia [77,78], autop- hagy [79], immune cell function [80], cellular differentiation [81], integrins [82], as well as oncogenes signalling [83]. PubMed:24563850
Our previous study [23] had shown that trehalose induces autophagy in primary neurons and in an N2a cell model of tauopathy, and efficiently reduces the level of MAPT and MAPT aggregation. PubMed:30145931
In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28]. PubMed:30145931
In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28]. PubMed:30145931
In contrast, chlorpromazine, which is a typical antipsychotic agent, induces autophagy by inhibiting the Akt/mTOR pathway PubMed:30061532
Higher levels of ROS biomarkers are characteristic of AD patients in clinical and preclinical studies, resulting in the alteration of membrane proper- ties, such as fluidity, ion transport, enzyme activities, protein cross- linking, tau protein hyperphosphorylation, autophagic dysfunction and eventually neuron cell death [20]. PubMed:27288790
Recently, in vitro studies on the effects of second-generation, atypical antipsychotics demonstrated that sertindole and clozapine are potent autophagy inducers in both neuronal and non-neuronal cell lines PubMed:30061532
Similar to pimozide, clozapine activates the autophagy process via the AMPK–ULK1–Beclin1 pathway, as evidenced by increased levels of autophagy markers (i.e., LC3-II and Atg5–Atg12 conjugate); increased phosphorylation of AMPK and its downstream substrates, namely ULK1 and beclin1; and an increased number of autophagosomes in the frontal cortex in clozapine-treated rats PubMed:30061532
In line with this, METH produces ultrastructural alterations reflecting dysfunctional autophagy flux, which are DA-dependent PubMed:30061532
In line with this, METH produces ultrastructural alterations reflecting dysfunctional autophagy flux, which are DA-dependent PubMed:30061532
Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. PubMed:30061532
For instance, the increase in autophagy flux induced by pimozide occurs along with a depression of phosphorylated tau in a transgenic mouse model of AD PubMed:30061532
Recently, in vitro studies on the effects of second-generation, atypical antipsychotics demonstrated that sertindole and clozapine are potent autophagy inducers in both neuronal and non-neuronal cell lines PubMed:30061532
Noteworthy, genetic ablation of autophagy was shown to produce an extremely powerful DA release upon electrical stimuli, suggesting that autophagy is key to restrain DA release both upon basal neural activity and mostly after rapamycin-induced autophagy PubMed:30061532
Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. PubMed:30061532
Notably, high-throughput image-based screens performed by Zhang et al. (2007) [60] on a human glioblastoma H4 cell line expressing human LC3 coupled with green fluorescent protein (GFP) led us to disclose that three typical antipsychotic drugs (fluspirilene, trifluoperazine, and pimozide) are effective autophagy inducers. PubMed:30061532
These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2) PubMed:30061532
In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532
In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532
Therefore, disruption of DISC1 activity, due to genetic rearrangements (i.e., balanced (1;11) (q42;q14) chromosomal translocation) or missense mutations, produces schizophrenic-like behavior, which is bound to enhanced Akt activity, over-activation of mTOR signaling, and depressed autophagy PubMed:30061532
This is key, because abnormal stimulation of D1R and subsequent signaling cascades were recently shown to produce an over-activation of mTOR and inhibition of the autophagy machinery PubMed:30061532
Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation PubMed:30061532
In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134–136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137]. PubMed:30061532
The biological implication behind an impairment of microtubule dynamics is confirmed in post-mortem schizophrenic brain samples, as well as in mouse models of schizophrenia, where mTOR-dependent autophagy dysfunction is accompanied by an altered gene expression and protein levels of the microtubule-associated protein 6 (MAP6) PubMed:30061532
In particular, pimozide provides an mTOR-independent autophagy induction, because it directly activates AMPK1, which in turn promotes autophagy through the phosphorylation of ULK1 PubMed:30061532
In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532
A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532
Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia PubMed:30061532
A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532
Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients PubMed:30061532
Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381
Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381
ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381
Likewise, mechanistic target of rapamycin (Mtor), which has been linked to cellular regulation, protein translation, autophagy, and the actin cytoskeleton (43–45), was also found to be regulated by ADNP and NAP PubMed:30106381
a-syn accumulation has been linked to autophagic and lysosomal dysfunction, which may in turn lead to a-syn aggregation and production of more detrimental oligomers. PubMed:28803412
Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 . PubMed:30116051
Mutant Htt is cleared by autophagy, but it compromises the ALN because of decreased cargo load- ing and impaired autophagosome formation and trans- port 55,56,68,92 . PubMed:30116051
PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553
PSA has been shown to be involved in the induction of autophagy and specifically the formation of autophagosomes, in a model of overexpressed mutant huntingtin (32). Thus, the in vivo effects of PSA on promoting tau clearance may relate to its ability to modulate the key clearance pathway for abnormal and aggregated proteins (to be described in more detail below). PubMed:24027553
Tau proteins in a variety of forms are reported as degraded through the autophagy-lysosome system. PubMed:23528736
Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56 PubMed:26195256
It has been indicated that intracellular tau proteins are also degraded by autophagy and proteasomal pathways (Wang and Mandelkow 2012) PubMed:29626319
Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319
Neuronal PAS domain protein 4 has been found to facilitate the autophagic clearance of endogenous total and phosphorylated tau in cortical neurons of rats PubMed:29626319
Furthermore, autophagy can regulate both apoptosis and inflammasome assembly, and, depending on the conditions, can be either pro- or anti-apoptotic104 PubMed:23702978
Furthermore, autophagy can regulate both apoptosis and inflammasome assembly, and, depending on the conditions, can be either pro- or anti-apoptotic104 PubMed:23702978
For inflammasome activation and IL-1β release, autophagy is a negative regulator: PubMed:23702978
For inflammasome activation and IL-1β release, autophagy is a negative regulator: PubMed:23702978
Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011). PubMed:22020111
Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300
Even early autophagic activation may become impaired due to progressively diminishing lysosomal clearance of substrates. PubMed:29758300
Although the UPS is accountable for the degradation of up to 80–90% of proteins, misfolded proteins and aggregates are too large to be processed through the proteasome barrel and can impede UPS function by physical occlusion, leaving autophagic-lysosomal breakdown as the only effective pathway to clear these proteins [25,26] PubMed:29758300
Although the UPS is accountable for the degradation of up to 80–90% of proteins, misfolded proteins and aggregates are too large to be processed through the proteasome barrel and can impede UPS function by physical occlusion, leaving autophagic-lysosomal breakdown as the only effective pathway to clear these proteins [25,26] PubMed:29758300
Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300
TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89]. PubMed:29758300
Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300
These experimental differences may be attributed to the intricate interplay between the UPS and autophagy, as α-synuclein is degraded by both proteolytic systems [62,63]. PubMed:29758300
Decreased autophagy in the diseased brain may contribute to aberrant lipid accumulation that occurs along with an increased incidence of the metabolic syndrome in aged humans [76] PubMed:29758300
While autophagic-lysosomal degradation is more commonly associated with protein degradation, it serves to degrade all cellular material including carbohydrates and lipids. PubMed:29758300
In addition to the direct modulation of protein generation, lipids can also influence the levels of proteins through autophagic clearance; for instance, increasing lipid contents has been shown to impair autophagy [72]. PubMed:29758300
While autophagic-lysosomal degradation is more commonly associated with protein degradation, it serves to degrade all cellular material including carbohydrates and lipids. PubMed:29758300
Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53] PubMed:29758300
A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300
The lysosomal system, and specifically the autophagic pathway, is the principal mechanism for degrading proteins with long half-lives and is the only system in cells for degrading organelles and large protein aggregates or inclusions. PubMed:22908190
Recently, protein aggregates and certain organelles have been shown to be tagged with ubiquination for selective removal by autophagy (Narendra et al. 2009; Dikic et al. 2010; Youle et al. 2011), a degradative process previously believed to be only nonselective PubMed:22908190
Autophagy is the cell’s principal degradative pathway for eliminating unwanted organelles and long-lived proteins and for clearing damaged, aggregated, or obsolete proteins (Wong et al. 2010). PubMed:22908190
The lysosomal system, and specifically the autophagic pathway, is the principal mechanism for degrading proteins with long half-lives and is the only system in cells for degrading organelles and large protein aggregates or inclusions. PubMed:22908190
Recently, protein aggregates and certain organelles have been shown to be tagged with ubiquination for selective removal by autophagy (Narendra et al. 2009; Dikic et al. 2010; Youle et al. 2011), a degradative process previously believed to be only nonselective PubMed:22908190
Autophagy is the cell’s principal degradative pathway for eliminating unwanted organelles and long-lived proteins and for clearing damaged, aggregated, or obsolete proteins (Wong et al. 2010). PubMed:22908190
Interdependence of the proteasome and lysosomal system is also suggested by observations that, when proteasome activity is inhibited, proteins accumulate that become substrates for autophagy (Fortun et al. 2003) PubMed:22908190
Inhibiting autophagy by genetically deleting components of the sequestration machinery causes ubiquitinated protein aggregates to appear in neurons, reflecting additional negative effects on the UPS (Korolchuket al. 2009a,b). PubMed:22908190
Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD PubMed:22908190
For example, immunocytochemistry showing the presence of K63- linked polyubiquitin in a fraction of the NFTs in AD cortex (Paine et al. 2009) suggests an active involvement of autophagy in the mechanism of AD. PubMed:22908190
Similar autophagy pathology is observed when lysosomal proteolysis is inhibited (Ivy et al. 1984; Koike et al. 2005; Yang et al. 2008). PubMed:22908190
AVs are also enriched in APP substrates and secretases and, during autophagy, Ab peptide is generated from APP (Yu et al. 2005), although it is subsequently degraded in lysosomes under normal circumstances (Heinrich et al. 1999; Bahr et al. 2002; Florez-McClure et al. 2007). PubMed:22908190
Chronic low-level stimulation of autophagy through peripheral administration of rapamycin or other agents (Tian et al. 2011), or enhancing lysosomal proteolysis selectively (Sun et al. 2008; Yang et al. 2011), can markedly diminish Ab levels and amyloid load in APP transgenic mice, underscoring the importance of lysosomal clearance of Ab. PubMed:22908190
Consistent with these findings, rapamycin induction of autophagy reduces tau pathology in the triple transgenic AD-mouse model (Caccamo et al. 2010), whereas in other models, autophagic–lysosomal dysfunction amplifies tau pathology and tau neurotoxicity (Hamano et al. 2008; Khurana et al. 2010). PubMed:22908190
Consistent with these findings, rapamycin induction of autophagy reduces tau pathology in the triple transgenic AD-mouse model (Caccamo et al. 2010), whereas in other models, autophagic–lysosomal dysfunction amplifies tau pathology and tau neurotoxicity (Hamano et al. 2008; Khurana et al. 2010). PubMed:22908190
Ab42-induced neurotoxicity is further enhanced by autophagy activation and is partially rescued by autophagy inhibition. PubMed:22908190
Autophagy may also modulate synaptic plasticity, which involves structural remodeling of nerve terminals (Boland et al. 2006) and the trafficking and degradation of receptors and other synaptic proteins (Leil et al. 2004; Rowland et al. 2006). PubMed:22908190
The PN branch of degradation includes the ubiquitin- proteasome system (UPS) and machinery of autophagy (23, 196–200). PubMed:23746257
Aggregated proteins that cannot be un- folded for proteasomal degradation may be removed by autophagy and lysosomal/vacuolar degradation. PubMed:23746257
Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136
Autophagy, by contrast, is primarily responsible for degrading long-lived proteins and maintaining amino acid pools in the setting of chronic starvation, although its contribution to the degradation of defective proteins may equal that of the UPS. PubMed:18930136
Autophagy, by contrast, is primarily responsible for degrading long-lived proteins and maintaining amino acid pools in the setting of chronic starvation, although its contribution to the degradation of defective proteins may equal that of the UPS. PubMed:18930136
“Autophagy”, literally “self-eating”, describes a catabolic process in which cell constituents such as organelles and proteins are delivered to the lysosomal compartment for degradation. PubMed:18930136
“Autophagy”, literally “self-eating”, describes a catabolic process in which cell constituents such as organelles and proteins are delivered to the lysosomal compartment for degradation. PubMed:18930136
Recent advances have demonstrated that autophagy also serves a surprisingly diverse array of additional functions, including organelle clearance, antigen presentation, elimination of microbes, as well as regulation of development and cell death [9]. PubMed:18930136
“Autophagy”, literally “self-eating”, describes a catabolic process in which cell constituents such as organelles and proteins are delivered to the lysosomal compartment for degradation. PubMed:18930136
“Autophagy”, literally “self-eating”, describes a catabolic process in which cell constituents such as organelles and proteins are delivered to the lysosomal compartment for degradation. PubMed:18930136
Autophagy is an evolutionarily conserved process whose primary task in lower organisms is the maintenance of metabolic homeostasis in the face of changing nutrient availability [8]. PubMed:18930136
Recent advances have demonstrated that autophagy also serves a surprisingly diverse array of additional functions, including organelle clearance, antigen presentation, elimination of microbes, as well as regulation of development and cell death [9]. PubMed:18930136
Recent advances have demonstrated that autophagy also serves a surprisingly diverse array of additional functions, including organelle clearance, antigen presentation, elimination of microbes, as well as regulation of development and cell death [9]. PubMed:18930136
Recent advances have demonstrated that autophagy also serves a surprisingly diverse array of additional functions, including organelle clearance, antigen presentation, elimination of microbes, as well as regulation of development and cell death [9]. PubMed:18930136
It has also been suggested that autophagy plays a role in the initiation or progression of some neurodegenerative diseases [20]. PubMed:18930136
For example, in a Drosophila model of X-linked spinobulbar muscular atrophy (SBMA), a polyglutamine disease, degeneration was strongly enhanced by genetic inhibition of autophagy [50]. PubMed:18930136
Insight into the role of autophagy in neurodegeneration has been provided by studies indicating that: 1) some neurodegenerative disease-related proteins are degraded by autophagy, 2) impairment of autophagy promotes neurodegeneration in animal models and several human neurodegenerative diseases, and 3) manipulation of autophagy modifies phenotypes in animal models of neurodegeneration. PubMed:18930136
That neurodegenerative disease-causing proteins are frequently degraded by autophagy was demonstrated by a series of in vitro studies which showed that pharmacological induction or inhibition of macroautophagy alters the rate of turnover of a number of disease-related proteins including polyglutamine-expanded proteins, polyalanine-expanded proteins, as well as wild type and mutant forms of α-synuclein [25,26] PubMed:18930136
That neurodegenerative disease-causing proteins are frequently degraded by autophagy was demonstrated by a series of in vitro studies which showed that pharmacological induction or inhibition of macroautophagy alters the rate of turnover of a number of disease-related proteins including polyglutamine-expanded proteins, polyalanine-expanded proteins, as well as wild type and mutant forms of α-synuclein [25,26] PubMed:18930136
In the case of α-synuclein, for example, Webb et al. concluded that soluble forms of the disease protein are efficiently degraded by the UPS, while aggregated or oligomeric α-synuclein require autophagy for clearance [26]. PubMed:18930136
In the case of α-synuclein, for example, Webb et al. concluded that soluble forms of the disease protein are efficiently degraded by the UPS, while aggregated or oligomeric α-synuclein require autophagy for clearance [26]. PubMed:18930136
It is becoming increasingly evident that the autophagy-lysosomal system is essential to neuronal homeostasis, and may in some settings be neuroprotective PubMed:18930136
It is becoming increasingly evident that the autophagy-lysosomal system is essential to neuronal homeostasis, and may in some settings be neuroprotective PubMed:18930136
Similarly, in transgenic mice expressing amyloid precursor protein, a mouse model of Alzheimer’s disease, genetic inhibition of autophagy by heterozygous depletion of beclin-1 results in enhancement of neurodegeneration [51]. PubMed:18930136
It has now been established that clearance of misfolded proteins from aggresomes is mediated at least in part by autophagy, implicating this pathway as a compensatory mechanism for degrading misfolded proteins when the proteasome is impaired [27,64,71,73]. PubMed:18930136
In addition to aggresome formation, impairment of the UPS in vitro has been found to induce autophagy [63,64]. PubMed:18930136
Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136
Our previous work showed that inhibition of either the proteasome or autophagy in primary neurons induces pronounced neurotoxicity [23,24], making it impossible to address this issue in conventional neuron cultures. PubMed:30145931
In controls, the fraction of MAPT-containing dendrites on the neuritic side was low (~14%), but local treatment with inhibitors of either autophagy (wortmannin [Fig. 3B], bafilomycin A 1 [Fig. S3A]) or the proteasome (epoxomicin [Fig. 3C], lactacystin [Fig. S3B]) caused a pronounced 4-to 5-fold increase of MAPT-containing dendrites (to levels of ~50-76%) (Fig. 3D). PubMed:30145931
Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931
Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931
The two major pathways for protein degradation in cells are through the ubiquitin-proteasome system and the autophagy-lysosome system [10, 11], both of which have been implicated in tau degradation in AD [12]. PubMed:25374103
Remarkably, further investigation on the autophagy pathway revealed that all these misfolded proteins are autophagy substrates depending on mTOR activity PubMed:30061532
Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation PubMed:30061532
Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation PubMed:30061532
The relevance of autophagy for sustaining these mTOR-induced effects is confirmed by drugs inducing autophagy independently of mTOR activation PubMed:30061532
In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134–136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137]. PubMed:30061532
This confirms our previous studies showing that both genetic and pharmacological autophagy inhibition worsen the effects of METH administration PubMed:30061532
Noteworthy, genetic ablation of autophagy was shown to produce an extremely powerful DA release upon electrical stimuli, suggesting that autophagy is key to restrain DA release both upon basal neural activity and mostly after rapamycin-induced autophagy PubMed:30061532
These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2) PubMed:30061532
These findings strongly suggest that an autophagy dysfunction acts both at pre- and post-synaptic level to alter DA neurotransmission during both METH administration and schizophrenia (Figure 2) PubMed:30061532
Remarkably, the identification of rare genetic variants of ULK1 in a cohort of schizophrenic patients by means of exome sequence analysis strengthens the idea of a key role of both disrupted mTOR signaling and autophagy in the pathophysiology and susceptibility to schizophrenia PubMed:30061532
A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532
Later on, further analysis reported a disruption of the autophagy pathway also in the hippocampus of post-mortem schizophrenic patients PubMed:30061532
In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532
In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532
In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1, ULK2, ATG3), which were significantly down-regulated compared with controls PubMed:30061532
A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms PubMed:30061532
Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381
ADNP expression in lymphocytes correlates with inflammation levels (36), disease state, and autophagy (13), as well as intelligence (40). PubMed:30106381
Additionally, given that ADNP and NAP are linked with autophagy (13), cell adhesion (35), immune response (36), autism (6, 13, 15, 17, 27), and synapse-related processes (6), the analysis included several representative genes pertaining to these processes PubMed:30106381
Likewise, mechanistic target of rapamycin (Mtor), which has been linked to cellular regulation, protein translation, autophagy, and the actin cytoskeleton (43–45), was also found to be regulated by ADNP and NAP PubMed:30106381
Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.