UBB+ 1-capped polyUb chains are resistant to deubiquitination and inhibit proteasomal activity, which may mediate neurodegeneration through mitochondrial stress and p53 activation in neurites (Tan et al., 2007).
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).
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.
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).
Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005).
Autophagy inducers, including rapamycin (Fig. 3A), facilitate the degradation of insoluble forms of tau and also protect against its toxicity in Drosophila (Berger et al., 2006).
Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD.
Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008).
PHF-tau isolated from human AD brains in the soluble state was not degraded by the proteasome but instead functioned as an inhibitor of its activity (Keck et al., 2003).
A Ub with a 19-residue C-terminal extension from the UBB gene, or UBB+1 (Fig.2A) is selectively expressed in the brains of AD patients (van Leeuwen et al.,1998) and is often found to be accumulated in NFT in Alzheimer’s disease and other tauopathies
For example, the small molecule IU1 was recently identified from a high-throughput screen as a potent and selective inhibitor of USP14,
In a cell-based assay, IU1 treatment increased proteasomal activity to result in accelerated degradation rates of tau and oxidatively damaged proteins.
Oxidative stress also upregulates autophagy induction, which limits the production of reactive oxygen species from dysfunctional mitochondria.
Tau proteins in a variety of forms are reported as degraded through the autophagy-lysosome system.
Aging, a major risk factor for AD, affects both the UPS and autophagy.
Several E3 Ub ligases, such as CHIP, Parkin, RNF182, may have roles in AD and other neurodegenerative diseases (Shimura et al., 2004; Khandelwal et al., 2011; Lei et al., 2012).
Further evidence of UPS-mediated tau degradation came from the identification of the tau E3 ligase, which is the carboxyl terminus of the Hsc70–interacting protein (CHIP)–Hsc70 complex, with UbcH5B as the E2 enzyme (Petrucelli et al., 2004; Shimura et al., 2004).
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.
Another DUB known to be mutated in familial neurodegenerative diseases is Ataxin-3 in the polyglutamine (polyQ) spinocerebellar ataxia type 3 (Kawaguchi et al., 1994).
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).
Cathepsin D, a lysosomal protease, exhibited the capacity to degrade tau proteins in cultured hippocampal slices (Bednarski and Lynch, 1996).
Moreover, constitutive inactivation of p62 in mice resulted in aggregated tau proteins with Lys63–Ub chains (Babu et al., 2008).
The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ).
Mutations in ubiquitin C-terminal hydrolase L1 (UCH-L1) have been proposed to have a role in various neurodegenerative diseases including AD, although the causality of mutations in this gene in Parkinson’s disease is now considered doubtful (Healy et al., 2006; Hutter et al., 2008).
Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B).
All three proteolytic activities have been reported to be decreased in AD brains (Keller et al., 2000).
Pathologically, the AD brains show both accumulated autophagosomes and autolysosomes, suggesting the basal autophagy process in neurons is abnormal in AD (Fig. 3A).
The accumulated autophagic vacuoles in AD mainly reflect defected lysosomal clearance instead of induced autophagy.
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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.