Pathologic connection between LRRK2 & chaperone-mediated autophagy
Mutations in the LRRK2 gene are the most common cause of familial form of Parkinson’s disease (PD). LRRK2 exerts its toxic effect partly by blocking chaperone-mediated autophagy (CMA).
Wild type LRRK2 is readily digested by the lysosomes via CMA, however, its disease-causing variants are poorly degraded by this pathway (Orenstein et al., Nature Neuroscience 2013).
CMA-mediated degradation of LRRK2 requires binding to cytosolic chaperone hsc70, and recognition of hsc70-LRRK2 complex by LAMP2A on the lysosomal membrane. This interaction leads to the oligomerization of LAMP2A which forms a translocation complex that allows lysosomal import of LRRK2 and its proteolytic degradation within this compartment.
PD-related LRRK2 mutants block the oligomerization of LAMP2A and the formation of CMA translocation complex leading to impaired degradation and accumulation of LRRK2 and other CMA substrates including another PD-associated protein, α-synuclein. Interestingly, the toxic effect of LRRK2 on CMA is also manifested in cells that express high levels of the wild type protein, highlighting the need to tightly regulate its intracellular levels.