PubMed: 23528736

Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system.
Progress in neurobiology
Lee JH | Lee MJ | Rubinsztein DC

Evidence 705108a6f4

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).

Evidence 1dec62e7ce

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).

Evidence ff85a2f95a

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.

Evidence b0c44b4279

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).

Evidence a5f438a94f

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).

Evidence d41288fcc7

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).

Evidence 4e370a7ef7

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD.

Evidence abaae69621

Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008).

Evidence dff61d4399

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).

Evidence d5a0496124

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

Evidence 25cf0f73ac

For example, the small molecule IU1 was recently identified from a high-throughput screen as a potent and selective inhibitor of USP14,

Evidence 19a3b84608

In a cell-based assay, IU1 treatment increased proteasomal activity to result in accelerated degradation rates of tau and oxidatively damaged proteins.

Evidence 6a5cf95b7e

Oxidative stress also upregulates autophagy induction, which limits the production of reactive oxygen species from dysfunctional mitochondria.

Evidence 3524945be7

Tau proteins in a variety of forms are reported as degraded through the autophagy-lysosome system.

Evidence 8fa66873f3

Aging, a major risk factor for AD, affects both the UPS and autophagy.

Evidence c13de882d5

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).

Evidence 5ff6809e5c

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).

Evidence 338ca0d70b

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.

Evidence 808a350143

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).

Evidence 511db526b0

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).

Evidence 9c87203d59

Cathepsin D, a lysosomal protease, exhibited the capacity to degrade tau proteins in cultured hippocampal slices (Bednarski and Lynch, 1996).

Evidence 1cb19ece98

Moreover, constitutive inactivation of p62 in mice resulted in aggregated tau proteins with Lys63–Ub chains (Babu et al., 2008).

Evidence 302fadf696

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ).

Evidence bf0cf98891

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).

Evidence 70c8a76b32

Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B).

Evidence 4c6b299c9e

All three proteolytic activities have been reported to be decreased in AD brains (Keller et al., 2000).

Evidence 120afff72c

Pathologically, the AD brains show both accumulated autophagosomes and autolysosomes, suggesting the basal autophagy process in neurons is abnormal in AD (Fig. 3A).

Evidence e0f7ba6b6b

The accumulated autophagic vacuoles in AD mainly reflect defected lysosomal clearance instead of induced autophagy.


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