p(HGNC:SNCA)
In addition, other proteins, e.g., alphaSYN (Waelter et al., 2001) and the transcriptional cofactor CREB binding protein (CBP) (Jiang et al., 2003),colocalize with the protein inclusions PubMed:14556719
Wild-type alphaSYN is monomeric, but at high concentration, it oligomerizes to beta-pleated sheets known as protofibrils PubMed:14556719
Of note is that overexpression of Parkin also suppresses alpha-synuclein (alphSYN) toxicity, suggesting that Parkin may play a role in regulating this protein as well (see below) PubMed:14556719
Of note is that overexpression of Parkin also suppresses alpha-synuclein (alphSYN) toxicity, suggesting that Parkin may play a role in regulating this protein as well (see below) PubMed:14556719
Parkin also ubiquitinates Synphilin-1, a protein of hitherto unknown function that contains a coiled-coiled domain and an ATP/GTP binding motif and that associates with alphaSYN (Chung et al., 2001). PubMed:14556719
Therefore, patients with AR-JP—who cannot degrade it because of the mutation in the Parkin E3 (see above)—develop neurodegeneration PubMed:14556719
USP19 promoted the secretion of a-syn, suggesting that MAPS is an unconventional secretion pathway utilized by a-syn, particularly under conditions of proteasomal impairment, which has been repeatedly linked to Parkinson’s disease. PubMed:28803412
Over the past two decades, the pre-synaptic protein alphasynuclein (a-syn) has been irrefutably tied to the neurodegenerative disorder Parkinson’s disease. PubMed:28803412
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
It increased expression of βGCase, normalized autophagy and accelerated degradation of α-synuclein in a stem cell model of dopaminergic neurons derived from patients with PD bearing mutations in βGCase 200 . PubMed:30116051
Ambroxol, which also decreased ER stress in D. mela- nogaster 201 , reduced α-synuclein levels in overexpress- ing, transgenic mice 202 . PubMed:30116051
Enhancing auto- phagy with rapamycin reduced levels of α-synuclein, FUS and Htt 130–132 . PubMed:30116051
Tau, α-synuclein and TDP43 are substrates for CMA degradation, as are amyloid precursor protein (APP) but not amyloid-β fragment 42 (Aβ42) itself 3,45–47,48 . PubMed:30116051
CMA dysfunction in PD favours the accumulation of α- synuclein and leads to inactivation of the dopaminergic neuron survival factor, myocyte-specific enhancer factor 2D (MEF2D) 2,45,47,55 . PubMed:30116051
Calpain inhibition by cal- pastatin or pharmacological agents also confers neuropro- tective effects in other NDA models, including improved clearance of tau, α-synuclein and SOD1 (REFS54,106,107) . PubMed:30116051
Finally, the extracellular and intracellular serine protease neurosin (also known as KLK6) cleaves α- synuclein. PubMed:30116051
Nonetheless, overexpression of LAMP2A accelerated CMA-related clearance of α-synuclein and afforded pro- tection of dopaminergic neurons 45 , and several routes to potential pharmacological exploitation exist. PubMed:30116051
Plasmin also degrades α-synuclein to retard intercellular spreading 262 . PubMed:30116051
Cuervo et al. have revealed a distinct interaction of wild-type and mutant α-synuclein proteins with CMA [64] PubMed:29758300
While wild-type α-synuclein protein efficiently clears via CMA, the pathogenic A53T and A30P variants remain bound to LAMP-2, blocking lysosomal degradation by preventing binding of other substrate complexes to the receptor [64]. 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
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
Since the initial finding of proteasome-dependent degradation of α-synuclein [58], significant efforts have been made to clarify the modes of α-synuclein metabolism PubMed:29758300
While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300
In 1997, a-synuclein was shown to be the principal component of Lewy bodies (Spillantini et al. 1997). The accumulated a-synuclein was then shown to be ubiquitinated (Hasegawa et al. 2002). PubMed:22908190
CMA has also been found to contribute to the degradation of α-synuclein [29]. PubMed:18930136
For example, α-synuclein is degraded at least in part by CMA [29]. PubMed:18930136
The neuronal protein α-synuclein, for example, can be degraded by the UPS, macroautophagy and chaperone-mediated autophagy [26,29]. 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
The neuronal protein α-synuclein, for example, can be degraded by the UPS, macroautophagy and chaperone-mediated autophagy [26,29]. 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
The neuronal protein α-synuclein, for example, can be degraded by the UPS, macroautophagy and chaperone-mediated autophagy [26,29]. PubMed:18930136
The accumulation of α‐synuclein gives rise to the formation of a nucleus for the accumulation of other proteins, which ultimately leads to the formation of Lewy bodies (within the dopamine secreting cells). PubMed:30663117
This protein is commonly found in the presynaptic terminus and is a factor in the transmission of synaptic dopaminergic neurons. PubMed:30663117
Two miRNAs that play an important role in regulating α‐synuclein expression are miR‐153 and miR‐7 PubMed:30663117
That is, in the event that miRNAs regulating α‐synuclein that reduce its accumulation (including miR‐153, miR‐7, miR‐132, and miR‐133‐b) are decreased, the progression of PD will be accelerated. PubMed:30663117
These two miRNAs downregulate the α‐synuclein by binding to the 3′‐UTR portion in the mRNA transcribed from SNCA. PubMed:30663117
In an experiment conducted to investigate this, pre‐miR‐34b and premiR‐ 34c were introduced into human dopaminergic SH‐SY5S cells and it was found that the amount of α‐synuclein protein had decreased significantly. PubMed:30663117
These two miRNAs downregulate the α‐synuclein by binding to the 3′‐UTR portion in the mRNA transcribed from SNCA. PubMed:30663117
In an experiment conducted to investigate this, pre‐miR‐34b and premiR‐ 34c were introduced into human dopaminergic SH‐SY5S cells and it was found that the amount of α‐synuclein protein had decreased significantly. PubMed:30663117
Two miRNAs that play an important role in regulating α‐synuclein expression are miR‐153 and miR‐7 PubMed:30663117
It has been shown that miR‐7 inhibition increases the expression of α‐synuclein PubMed:30663117
That is, in the event that miRNAs regulating α‐synuclein that reduce its accumulation (including miR‐153, miR‐7, miR‐132, and miR‐133‐b) are decreased, the progression of PD will be accelerated. PubMed:30663117
miR‐132 is another miRNA that has a regulatory effect on α‐synuclein. The downregulation of this miRNA results in the accumulation of α‐synuclein protein PubMed:30663117
miR‐132 is another miRNA that has a regulatory effect on α‐synuclein. The downregulation of this miRNA results in the accumulation of α‐synuclein protein PubMed:30663117
That is, in the event that miRNAs regulating α‐synuclein that reduce its accumulation (including miR‐153, miR‐7, miR‐132, and miR‐133‐b) are decreased, the progression of PD will be accelerated. PubMed:30663117
That is, in the event that miRNAs regulating α‐synuclein that reduce its accumulation (including miR‐153, miR‐7, miR‐132, and miR‐133‐b) are decreased, the progression of PD will be accelerated. PubMed:30663117
Cuervo et al. have revealed a distinct interaction of wild-type and mutant α-synuclein proteins with CMA [64] PubMed:29758300
Parkin also ubiquitinates Synphilin-1, a protein of hitherto unknown function that contains a coiled-coiled domain and an ATP/GTP binding motif and that associates with alphaSYN (Chung et al., 2001). PubMed:14556719
alphaSYN is a small, 140 amino acid residue protein that is thought to regulate/participate in dopamine neurotransmission/release via effects on vesicular storage PubMed:14556719
alphaSYN is a small, 140 amino acid residue protein that is thought to regulate/participate in dopamine neurotransmission/release via effects on vesicular storage PubMed:14556719
Wild-type alphaSYN is monomeric, but at high concentration, it oligomerizes to beta-pleated sheets known as protofibrils PubMed:14556719
Overexpression of wild-type, but in particular mutant alphaSYN in many cell types but not in all, induces apoptosis or sensitizes the cells to toxic agents, including proteasome inhibitors (see, for example, Lee et al.,2001a). PubMed:14556719
Instead, impairment of alphaSYN function may disturb ubiquitination of alphaSYN-associated proteins, such as Synphilin (Chung et al., 2001) and tyrosine hydroxylase (Doskeland and Flatmark, 2002), and thereby perturb neuronal homeostasis PubMed:14556719
Instead, impairment of alphaSYN function may disturb ubiquitination of alphaSYN-associated proteins, such as Synphilin (Chung et al., 2001) and tyrosine hydroxylase (Doskeland and Flatmark, 2002), and thereby perturb neuronal homeostasis PubMed:14556719
Instead, impairment of alphaSYN function may disturb ubiquitination of alphaSYN-associated proteins, such as Synphilin (Chung et al., 2001) and tyrosine hydroxylase (Doskeland and Flatmark, 2002), and thereby perturb neuronal homeostasis PubMed:14556719
In addition, other proteins, e.g., alphaSYN (Waelter et al., 2001) and the transcriptional cofactor CREB binding protein (CBP) (Jiang et al., 2003),colocalize with the protein inclusions PubMed:14556719
In contrast, α-synuclein overexpression impairs autophagy in mammalian cells and mice through reduced expression of RAB1A, thereby inhibiting autophagosome formation (88). 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
Over the past two decades, the pre-synaptic protein alphasynuclein (a-syn) has been irrefutably tied to the neurodegenerative disorder Parkinson’s disease. PubMed:28803412
While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300
Recent clinical and immunohistochemistry studies demonstrate the contribution of α-synuclein in the development of AD pathology PubMed:29758300
While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300
In 1997, a-synuclein was shown to be the principal component of Lewy bodies (Spillantini et al. 1997). The accumulated a-synuclein was then shown to be ubiquitinated (Hasegawa et al. 2002). PubMed:22908190
In 1997, a-synuclein was shown to be the principal component of Lewy bodies (Spillantini et al. 1997). The accumulated a-synuclein was then shown to be ubiquitinated (Hasegawa et al. 2002). PubMed:22908190
This protein is commonly found in the presynaptic terminus and is a factor in the transmission of synaptic dopaminergic neurons. PubMed:30663117
The accumulation of α‐synuclein gives rise to the formation of a nucleus for the accumulation of other proteins, which ultimately leads to the formation of Lewy bodies (within the dopamine secreting cells). PubMed:30663117
BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.
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.