Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Abstract

Parkinson disease (PD), once considered as a prototype of a sporadic disease, is now known to be considerably affected by various genetic factors, which interact with environmental factors and the normal process of aging, leading to PD. Large studies determined that the hereditary component of PD is at least 27%, and in some populations, single genetic factors are responsible for more than 33% of PD patients. Interestingly, many of these genetic factors, such as LRRK2, GBA, SMPD1, SNCA, PARK2, PINK1, PARK7, SCARB2, and others, are involved in the autophagy-lysosome pathway (ALP). Some of these genes encode lysosomal enzymes, whereas others correspond to proteins that are involved in transport to the lysosome, mitophagy, or other autophagic-related functions. Is it possible that all these factors converge into a single pathway that causes PD? In this review, we will discuss these genetic findings and the role of the ALP in the pathogenesis of PD and will try to answer this question. We will suggest a novel hypothesis for the pathogenic mechanism of PD that involves the lysosome and the different autophagy pathways.

Keywords: GBA; LAMP2A; LRRK2; Parkinson disease; SNCA; autophagy; genetics; lysosome; mitophagy.

Figure 1.

Genes involved in Parkinson disease and in the autophagy-lysosome pathway. Figure 1 depicts genes that are associated with Parkinson disease and their area of effect in the autophagy lysosome pathway. Genes that are also involved in any lysosomal function that is not one of the forms of autophagy are depicted above the lysosome.

Figure 2.

Hypothesized mechanism for GBA-associated lysosomal dysfunction in Parkinson disease. (A) In a normally functioning lysosome, GBA is associated with the inner part of the lysosomal membrane, and degrades glucocerebrosides to glucose and ceramide, thus controlling the proper composition of the membrane. The chaperone-mediated autophagy receptor, LAMP2A, is able to freely move out of lipid rafts, create complexes, and internalize SNCA into the lysosome for degradation. (B) Impaired GBA activity can affect the composition of the membrane, leading to an increased density of lipid rafts on the lysosomal membrane. In this scenario, it is more difficult for LAMP2A to create the complexes required for the internalization of SNCA into the lysosome, leading to SNCA accumulation. This effect of GBA impairment on the lysosomal membrane may interrupt other pathways, and affect macroautophagy and mitophagy, which will lead to the accumulation of damaged mitochondria and increased oxidative stress.