Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains

Álvarez, Lydia; Rodriguez-Oroz, María C.; Cooper, Jonathan M.; Caballero, Cristina; Ferrer, Isidró; Obeso, José A.; Schapira, Anthony H.V.

doi:10.1001/archneurol.2010.198

Cited by 492 publications

(458 citation statements)

References 40 publications

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“…Increased levels of LAMP-2A have been observed in the early stages of PD both in mouse models [54] and in brains of PD patients [52]. However, in advanced stages, reduced levels of LAMP-2A and hsc70 have been detected instead in the dopaminergic neurons of human brain regions [58]. In fact, there seems to be a good correlation between regional deficiency in LAMP-2A, used as a surrogate marker for CMA function, and the selective vulnerability of the brain regions to α-synuclein aggregation [59].…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

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Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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“…19,20 In the context of PD, decreased LAMP2A [21][22][23] and HSPA8/ HSC70 21 protein levels are detected in human post-mortem PD brains, which-given that age is the primary risk factor for disease development 24 -renders LAMP2A abundance a valid target for both disease pathogenesis and therapy. We have previously shown that RNA-interference targeting LAMP2A results in significant accumulation of SNCA in cultured neurons, 17 whereas overexpression of LAMP2A in cell culture models and in dopaminergic neurons of the substantia nigra pars compacta (SNpc) is able to fully rescue neurotoxicity associated with elevated SNCA protein burden.…”

Section: Introductionmentioning

confidence: 99%

Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats

et al. 2016

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Chaperone-mediated autophagy (CMA) involves the selective lysosomal degradation of cytosolic proteins such as SNCA (synuclein a), a protein strongly implicated in Parkinson disease (PD) pathogenesis. However, the physiological role of CMA and the consequences of CMA failure in the living brain remain elusive. Here we show that CMA inhibition in the adult rat substantia nigra via adeno-associated virusmediated delivery of short hairpin RNAs targeting the LAMP2A receptor, involved in CMA's rate limiting step, was accompanied by intracellular accumulation of SNCA-positive puncta, which were also positive for UBIQUITIN, and in accumulation of autophagic vacuoles within LAMP2A-deficient nigral neurons. Strikingly, LAMP2A downregulation resulted in progressive loss of nigral dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, increased astro-and microgliosis and relevant motor deficits. Thus, this study highlights for the first time the importance of the CMA pathway in the dopaminergic system and suggests that CMA impairment may underlie PD pathogenesis.

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“…This disagreement suggests that elimination of this ␣-syn mutant could be enhanced in normal physiological conditions and it might be affected in the context of aging or PD pathogenesis. This hypothesis is supported by several observations reporting a dramatic dysfunction of protein degradation pathway, notably the autophagy pathway, during aging (45,46) and in PD-diseased brains (47,48), which lead to protein accumulation and neuronal loss.…”

Section: Discussionmentioning

confidence: 58%

Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

Dahmene

Bérard

Oueslati

2017

Journal of Biological Chemistry

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Edited by Roger J. ColbranIncreasing lines of evidence support the causal link between ␣-synuclein (␣-syn) accumulation in the brain and Parkinson's disease (PD) pathogenesis. Therefore, lowering ␣-syn protein levels may represent a viable therapeutic strategy for the treatment of PD and related disorders. We recently described a novel selective ␣-syn degradation pathway, catalyzed by the activity of the Polo-like kinase 2 (PLK2), capable of reducing ␣-syn protein expression and suppressing its toxicity in vivo. However, the exact molecular mechanisms underlying this degradation route remain elusive. In the present study we report that among PLK family members, PLK3 is also able to catalyze ␣-syn phosphorylation and degradation in living cells. Using pharmacological and genetic approaches, we confirmed the implication of the macroautophagy on PLK2-mediated ␣-syn turnover, and our observations suggest a concomitant co-degradation of these two proteins. Moreover, we showed that the N-terminal region of ␣-syn is important for PLK2-mediated ␣-syn phosphorylation and degradation and is implicated in the physical interaction between the two proteins. We also demonstrated that PLK2 polyubiquitination is important for PLK2⅐␣-syn protein complex degradation, and we hypothesize that this post-translational modification may act as a signal for the selective recognition by the macroautophagy machinery. Finally, we observed that the PD-linked mutation E46K enhances PLK2-mediated ␣-syn degradation, suggesting that this mutated form is a bona fide substrate of this degradation pathway. In conclusion, our study provides a detailed description of the new degradation route of ␣-syn and offers new opportunities for the development of therapeutic strategies aiming to reduce ␣-syn protein accumulation and toxicity. Parkinson's disease (PD)2 is a neurodegenerative disorder characterized by the progressive loss of vulnerable neuronal populations in the brain and the accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (1, 2). These inclusions mainly consist of a presynaptic protein, ␣-synuclein (␣-syn) (3-5). Converging lines of evidence from neuropathological studies and experimental models support the central role of ␣-syn aggregation and toxicity in the pathogenesis of PD (3, 6). This ␣-syn abnormal accumulation is in part triggered by its gene duplications/triplications or by the impairment of its degradation (3, 6). Therefore, enhancing ␣-syn elimination may represent a viable therapeutic strategy for the treatment of PD and related disorders.However, the question on how ␣-syn is eliminated in vivo has yielded controversial results (7). Although some studies reported specific elimination of the monomeric and fibrillar ␣-syn forms by the ubiquitin-proteasome system (8 -10), others reported the degradation of this protein via the autophagy-lysosomal pathway, notably the chaperone-mediated autophagy (10 -12). This controversy and the lack of known selective routes for ␣-syn elimination precluded the development ...

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Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains

Abstract: To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD).

Cited by 492 publications

References 40 publications

Chaperone-mediated autophagy: roles in disease and aging

Chaperone-mediated autophagy: roles in disease and aging

Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats

Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

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