Abstract
Chaperone-mediated autophagy (CMA) represents a selective form of autophagy involved in the degradation of specific soluble proteins containing a pentapeptide motif that is recognized by a cytosolic chaperone able to deliver proteins to the lysosomes for degradation. Physiologically, CMA contributes to maintain crucial cellular functions including energetic balance and protein quality control. Dysfunctions in CMA have been associated to the pathogenesis of several neurodegenerative diseases characterized by accumulation and aggregation of proteins identified as CMA substrates. In particular, increasing evidence highlights the existence of a strong relationship between CMA defects and Parkinson’s disease (PD). Several mutations associated with familial forms of PD (SNCA, LRRK2, UCHL1 and DJ-1) have been demonstrated to block or reduce the activity of CMA, the main catabolic pathway for alpha-synuclein (asyn). CMA dysfunctions also leads to a mislocalization and inactivation of the transcription factor MEF2D that plays a key-role in the survival of dopaminergic neurons. Furthermore, reduced levels of CMA markers have been observed in post mortem brain samples from PD patients. The aim of this review article is to provide an organic revision of evidence for the involvement of CMA dysfunctions in the pathogenesis of PD. Updated findings obtained in patient’s specimens will be resumed, and results deriving from in vivo and in vitro studies will be discussed to evidence the current knowledge on the molecular mechanisms underlying CMA alterations in PD. Finally, the possibility of up-regulating CMA pathway as promising neuroprotective strategy will be considered.
Highlights
Chaperone-mediated autophagy (CMA) represents a selective form of autophagy involved in the degradation of specific soluble proteins containing a pentapeptide motif that is recognized by a cytosolic chaperone able to deliver proteins to the lysosomes for degradation
The accumulation of aggregated asyn has been related to defects in the two major protein catabolic systems (Xilouri et al, 2013b), the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), represented by macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy
Structural and functional alterations in the 20S proteasome subunit was demonstrated in post mortem substantia nigra of patients with sporadic Parkinson’s disease (PD) (McNaught and Olanow, 2003), and an increased number of autophagic vacuoles was found in melanized neurons of the substantia nigra in PD patients (Anglade et al, 1997)
Summary
In PD, alpha-synuclein (asyn) has been proposed as the central pathogenic protein, based on its identification as the main component of the intraneuronal aggregates, known as Lewy bodies, that represent a neuropathological hallmark of PD (Spillantini et al, 1997). The accumulation of aggregated asyn has been related to defects in the two major protein catabolic systems (Xilouri et al, 2013b), the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), represented by macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy. As the activity of UPS and ALP appears functionally connected, dysfunctions in one of these systems directly influence the other (Ding et al, 2007; Pandey et al, 2007; Korolchuk et al, 2009; Qiao and Zhang, 2009). Alterations of both UPS and macroautophagy have been reported in PD patients. After the demonstration that the efficiency of CMA pathway is crucial in regulating the intraneuronal levels of asyn (Cuervo et al, 2004; Mak et al, 2010), dysfunctions in this selective catabolic pathway have been identified as important pathogenic contributors to PD, as discussed
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