The Emerging Role of the Lysosome in Parkinson's Disease

Abstract

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson's disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson's disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

Keywords: Parkinson’s disease; autophagy; endocytosis; glucocerebrosidase; lysosomal storage diseases; lysosomes; α-synuclein.

Figure 1

The autophagy–lysosomal–endosomal system and the Parkinson’s disease (PD)-related proteins. Lysosomes are the terminal compartment where the intracellular macromolecules delivered by autophagy (orange) and the extracellular macromolecules delivered by endocytosis (green) are degraded. Three types of autophagy are described in mammalian cells: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy eliminates intracellular components including proteins and organelles; these substrates are enclosed in a double membrane vesicle called an autophagosome (APH) that can be directly fused with lysosomes forming an autolysosome (AL). Alternatively, an APH can also first fuse with a late endosome (LE) to form an amphisome (AMPH) before fusing with the lysosome in order to degrade the cargo. Extracellular macromolecules and plasma membrane components can also be eliminated inside the lysosomes by endocytosis. Following the internalization, cargo is transported to early endosomes (EEs), the initial sorting station in the endocytic pathway; then EEs can be sorted into different routes, recycled back to the cell surface, enter the retrograde pathway to be sent to the trans-Golgi network (TGN), or maturate into multivesicular bodies (MVB) or late endosomes (LE), which enter the degradation pathway, and finally merge with the lysosome. PD-related proteins are listed alongside the pathway or organelle in which they are involved.