Disease mechanisms as subtypes: Lysosomal dysfunction in the endolysosomal Parkinson's disease subtype

Abstract

Parkinson's disease (PD) remains one of the most prevalent neurodegenerative disorders. It has become increasingly recognized that PD is not one disease but a constellation of many, with distinct cellular mechanisms driving pathology and neuronal loss in each given subtype. Endolysosomal trafficking and lysosomal degradation are crucial to maintain neuronal homeostasis and vesicular trafficking. It is clear that deficits in endolysosomal signaling data support the existence of an endolysosomal PD subtype. This chapter describes how cellular pathways involved in endolysosomal vesicular trafficking and lysosomal degradation in neurons and immune cells can contribute to PD. Last, as inflammatory processes including phagocytosis and cytokine release are central in glia-neuron interactions, a spotlight on the role of neuroinflammation plays in the pathogenesis of this PD subtype is also explored.

Keywords: Alpha-synuclein; Endosomal trafficking; GBA1; Genetics; Inflammation; LRRK2; Lysosomes; Parkinson's disease; Phagocytosis; VPS35.