Fig. 1

Schematic representation of vesicular transport and lysosomal pathways affected in Parkinson's disease. Mutations in α-synuclein (α-syn), LRRK2 and VPS35 are associated with autosomal dominant Parkinson's disease (PD), whereas mutations in VPS13C and ATP10B are associated with autosomal recessive PD. Mutations in ATP13A2, PLA2G6, DNAJC6, ATP6AP2 and SYNJ1 are associated with autosomal recessive atypical parkinsonian syndromes (APS). α-Synuclein interacts with membranes and functions in intracellular trafficking transport pathways. LRRK2 phosphorylates a subgroup of Rab GTPases which are important regulators of intracellular vesicle transport. VPS35, VPS26 and VPS29 form the retromer cargo-recognition complex involved in intracellular retrograde transport from endosomes to the trans-Golgi network, and associates with a dimer of sorting nexins. VPS13C tethers between the endoplasmic reticulum and late endosomes and lysosomes, and transports glycerolipids between membranes. ATP10B and ATP13A2 are both late endosomal/lysosomal P-ATPases, involved respectively in glucosylceramide export, and polyamine export/Mn²⁺ and Zn²⁺ import. ATP6AP2 is a subunit of the vacuolar H+ ATPase (V-ATPase) involved in maintaining a low lysosomal pH. PLA2G6 hydrolyzes the sn-2 ester bond of membrane glycerophospholipids to yield free fatty acids and lysophospholipids and interacts with the retromer subunits VPS35 and VPS26. DNAJC6 and SYNJ1 both play a crucial role in the detachment of the clathrin-coat after clathrin-mediated endocytosis