The Role of Chaperone-Mediated Autophagy in Huntingtin Degradation

Qi, Lin; Zhang, Xingding; Wu, Jun; Lin, Fang; Wang, Jin; DiFiglia, Marian; Qin, Zheng

doi:10.1371/journal.pone.0046834

Cited by 117 publications

(110 citation statements)

References 49 publications

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“…Taken together, involvement of a lysosomal degradation pathway independent of autophagosomes, such as chaperone-mediated autophagy (37), is consistent with our results. A previous study has shown that as the length of the polyQ expansion increases, the ability of Htt to cross the lysosomal membrane is decreased suggesting that degradation through chaperone-mediated autophagy is impaired (37). This is consistent with our findings of decreased lysosomal activity in the presence of normal macroautophagy.…”

Section: Discussionsupporting

confidence: 92%

“…Huntingtin protein has a number of KFERQ-like sequences that are recognized by the heat shock cognate protein, Hsc70, and necessary for targeting to lysosomal degradation (36,37). In agreement with chaperone-mediated autophagic degradation of the N-terminal fragment of huntingtin (37), soluble Hsc70 protein levels are increased after induction of polyQ-Htt expression in our cell culture system (Fig. 4, H and I).…”

Section: Si Lowers the Number Of Visible Polyq-htt Inclusions-thesupporting

confidence: 68%

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scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

Lai

Lan

Hasan

et al. 2014

Journal of Biological Chemistry

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Background: Effects of scyllo-inositol, a modulator of misfolded protein accumulation, were tested in a cellular model of Huntington disease. Results: scyllo-Inositol lowered mutant huntingtin aggregation and decreased protein abundance through proteasomal and lysosomal degradation. Conclusion: scyllo-Inositol promotes mutant huntingtin degradation in a model of Huntington disease. Significance: In contrast to other compounds targeting mutant huntingtin aggregation and accumulation, scyllo-inositol promotes effective degradation.

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Section: Discussionsupporting

confidence: 92%

Section: Si Lowers the Number Of Visible Polyq-htt Inclusions-thesupporting

confidence: 68%

scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

Lai

Lan

Hasan

et al. 2014

Journal of Biological Chemistry

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“…The presence of a KFERQ-like motif is required to classify a protein as bona fide CMA substrate but, as described in the following sections, it is no longer sufficient because the same motif is also used by hsc70 to target cytosolic proteins to late endosomes via eMI (8). Hence, validation of proteins as CMA substrates requires experimental validation (5,34).The list of experimentally validated CMA substrates continues to grow and includes a broad variety of proteins involved in diverse cellular processes such as glycolytic enzymes (18,30,35,36), lipogenic enzymes (18), lipid droplet structural proteins (32), RNA modifying enzymes (37), proteins involved in calcium biology (38,39), transcription factors and their regulators (40)(41)(42), cell cycle regulators (25), ubiquitin-proteasome components (43), proteins involved in immune function (39 ,44), and in cell survival/cell death decisions (45)(46)(47)(48), as well as a subset of proteins that contribute to the pathogenesis of known neurodegenerative disorders (23,(26)(27)(28)43,(49)(50)(51).…”

Section: Characteristics Of the Proteome Amenable For Cma Degradationmentioning

confidence: 99%

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone

Tekirdağ

Cuervo

2018

Journal of Biological Chemistry

283

236

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A variety of mechanisms deliver cytosolic materials to the lysosomal compartment for degradation through autophagy. Here, we focus on two autophagic pathways, chaperone-mediated autophagy and endosomal microautophagy that rely on the cytosolic chaperone hsc70 for substrate targeting. Although hsc70 participates in triage of proteins for degradation by different proteolytic systems, the common characteristic shared by these two forms of autophagy, is that hsc70 binds directly to a specific five amino acids motif in the cargo protein for its autophagic targeting. We summarize the current understanding of the molecular machineries behind each of these types of autophagy.

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“…It was reported that the activity of CMA displayed constitutive compensatory upregulation in different cellular and transgenic mouse models of HD (20). Further investigations indicated that the Lamp2a and Hsc70 proteins played an important role in clearing Htt through the CMA pathway (21,22). Although the involvement of CMA in Htt metabolism has been suggested by other investigators, the essential effect of mutant Htt on CMA remains to be elucidated.…”

Section: Discussionmentioning

confidence: 96%

Maintenance of chaperone-mediated autophagy activity in cultured cells expressing mutant huntingtin

Wang

2014

Biomedical Reports

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Abstract. Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by mutant huntingtin (Htt) with an expanded polyglutamine tract. It has been reported that Htt regulates autophagy. However, it remains unclear whether mutant Htt affects chaperone-mediated autophagy (CMA). Our study aimed to investigate the effect of mutant Htt on CMA activity in cultured HEK293T cells. A HEK293T cell model of HD was produced by transient transfection of wild-type (20Q) or mutant (120Q) Htt plasmids. The effect of mutant Htt on two CMA components, lysosomal-associated membrane protein 2a (Lamp2a) and heat-shock cognate protein 70 (Hsc70), was determined by western blotting and immunofluorescent staining. We observed that mutant Htt did not significantly alter the expression of Lamp2a and Hsc70 when compared to normal Htt. These findings suggest that mutant Htt does not reduce CMA activity and that enhancing CMA activity to clear mutant Htt may be a novel strategy for the management of HD. IntroductionHuntington's disease (HD) is a progressive, autosomal dominant, neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat (>35 repeats) in the huntingtin (Htt) gene, which is translated into an expanded polyglutamine tract in the N-terminus of the Htt protein (1). The most obvious characteristic of HD is uncontrolled movement, dementia, emotional disturbance and early death, which often occur in middle age (2,3). These symptoms are associated with neuronal loss that preferentially occurs in medium-sized spiny neurons of the striatum and also extends to other brain regions during the late stages of the disease.Wild-type Htt is considered to possess a number of cellular functions, such as protein transport, vesicle trafficking and cytoskeletal anchoring. When Htt is mutated with an expanded polyglutamine tract (>36 glutamines), Htt becomes misfolded to induce gain of toxic function and may also lose its normal function. Mutant Htt appears to affect a variety of cellular functions, including intracellular signaling pathways (4), the protein degradation pathway (5) and the nuclear transcription and axon transport (6,7), resulting in degeneration of neuronal cells in the striatum and other brain regions.Clearing mutant Htt may be of value in preventing the pathogenesis and development of HD. In eukaryotic cells, there exist two systems of protein degradation, the ubiquitin-proteasome system and autophagy. Autophagy is a non-specific bulk degradation pathway for long-lived cytoplasmic proteins, protein complexes, or damaged organelles. There are three types of autophagy, namely macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Macroautophagy is considered to promote the degradation of Htt and clearance of aggregates. This is supported by several lines of evidence that rapamycin (an activator of autophagy) (8) and its several small molecular enhancers (9-11) may enhance the degradation of mutant Htt and reduce its toxicity. It is also important to investigate whether mu...

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The Role of Chaperone-Mediated Autophagy in Huntingtin Degradation

Cited by 117 publications

References 49 publications

scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone

Maintenance of chaperone-mediated autophagy activity in cultured cells expressing mutant huntingtin

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