Autophagy is a collection of cellular housekeeping processes known to be important in aging: many of the methods of altering metabolism to extend life include raised levels of autophagy in their effects. Artificially boosting autophagy beyond normal levels - or even just restoring it to youthful levels, as it declines with age - has for some years shown promise as a method of treating a range of age-related conditions, especially those that involve aggregations of misfolded proteins. Here is an example of this sort of work:
Abnormal aggregation of SNCA/α-synuclein plays a crucial role in Parkinson disease (PD) pathogenesis. SNCA levels determine its toxicity, and its accumulation, even to a small extent, may be a risk factor for neurodegeneration. One of the main pathways for SNCA degradation is chaperone-mediated autophagy (CMA), a selective form of autophagy, while aberrant SNCA may act as a CMA inhibitor.
We summarize our recent data showing that induction of CMA, via overexpression of the protein controlling its rate-limiting step, the lysosomal receptor LAMP2A, effectively decreases SNCA levels and ameliorates SNCA-induced neurodegeneration, both in neuronal cell culture systems and in the rat brain. Such findings suggest that modulation of LAMP2A and, consequently, CMA, represents a viable therapeutic target for PD and other synucleinopathies where SNCA accumulation and aggregation plays a fundamental role.