Figure 4.

PD-associated genes and their roles in mitochondria-lysosome crosstalk. (a) VPS35 is a key component of the retromer complex involved in the removal of DRP1 complexes from mitochondria to lysosomes or peroxisomes through MDVs. Mutant VPS35 enhances turnover of mitochondrial DRP1 complexes through MDVs and lysosomal degradation, accompanied by fragmented and dysfunctional mitochondria. PD-linked VPS35 mutant also leads to increased MUL1-mediated MFN2 degradation. (b) ATP13A2 mutations impair the autophagic process, leading to the cytosolic accumulation of α-syn. Sporadic PD patients show decreased levels of this protein, which is also found in Lewy bodies. (c) Mutant LRRK2 protein impinges on autophagosome formation, alters lysosomal pH and lysosomal calcium dynamics, resulting in impaired autophagosome–lysosome fusion and lysosome-mediated degradation.