. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol. 2010 Dec;67(12):1464-72. PubMed.


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  1. Given the rapidly accumulating evidence for defective autophagy as an important pathogenic process in Parkinson’s disease, it is surprising that almost no biochemical data had been collected on the lysosomal system in brains of PD patients until this interesting report by Alvarez-Erviti and colleagues. These authors have nicely demonstrated significant decreases in two key components of the chaperone-mediated autophagy (CMA) mechanism—Lamp2a and HSC70—in substantia nigra and amygdala of PD brains compared to control brains. The decreases were not observed in AD brain, indicating a degree of disease specificity. The human data add important support to evidence for autophagy deficits in models of PD involving mutant α-synuclein overexpression, where non-specific effects of elevated protein load on autophagy may be superimposed on disease-related effects. In this regard, α-synuclein overexpression elevates LAMP2a and HSC70 (this study and Mak et al., 2010), in contrast to PD, suggesting differences between the mechanisms operating in PD and in the mouse- and cell-overexpression models. It will be interesting to investigate these differences further, and the possible role of aging as part of the PD mechanism, given the observations by Ana Maria Cuervo and colleagues that CMA components decline in aging cells (Cuervo and Dice, 2000).

    Emerging evidence points to a broad protein and organelle clearance deficit in PD, which includes impaired mitophagy/macroautophagy and altered proteasome function. Although the authors interpret an observed increase in the levels of LC3-II in their PD brains as an induction of macroautophagy in response to CMA deficits, this finding is also consistent with slowed lysosomal clearance of autophagy substrates and decreased macroautophagic flux, which have, in fact, been reported in animal models of α-synucleinopathy by several investigators (Winslow et al., 2010; Spencer et al., 2009).

    In this respect, PD may resemble AD, where failure of lysosomal proteolysis caused by multiple genetic and environmental factors drives the marked autophagy deficit in this disease, greatly elevating the levels of waste proteins in affected neurons, including Aβ, β-CTF, and possibly toxic fragments of tau (Nixon et al., 2008; Wang et al., 2009; Yang et al., in press). Interestingly, in the PD brain, Alvarez-Erviti et al. show the greatest declines in CMA components within neurons with Lewy body inclusions, further highlighting the relationship between protein clearance failure and the appearance of hallmark protein aggregates within specific neuronal populations in aging-related neurodegenerative diseases.


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