Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall “lysosomal genetic burden”, namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD.

Rotenone Blocks the Glucocerebrosidase Enzyme and Induces the Accumulation of Lysosomes and Autophagolysosomes Independently of LRRK2 Kinase in HEK-293 Cells

“…ROT works as a strong inhibitor of complex I of the mitochondrial respiratory chain [ 18 ] via the inhibition of electron transfer from the iron–sulfur centers in complex I to ubiquinone, leading to the overproduction of reactive oxygen species (ROS) such as superoxide anion radical (O 2 − ), which dismutates into hydrogen peroxide (H 2 O 2 ) [ 19 ]. Interestingly, genetic forms of PD affect different mitochondria-associated proteins, such as leucine-rich repeat serine/threonine protein kinase 2 (LRRK2), as well as autophagy–lysosomal proteins (e.g., α-Syn; glucosylceramidase beta 1 (GBA1)), trigger mitochondrial alterations, OS, autophagy, and lysosomal dysfunction (e.g., [ 20 , 21 , 22 ]). Nonetheless, how LRRK2, α-Syn, and GBA1 proteins work alone or interact with each other during a loss of DAergic neurons is not yet clear [ 23 ].…”