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Pathologic connection between LRRK2 & chaperone-mediated autophagy

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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.

Learn more about BioLegend’s highly specific antibodies for LRRK2 and CMA-related proteins