Endolysosomal Dysfunction in Parkinson Disease: The Role of Disease Mutations in ATP13A2 and LRRK2.

[摘要] Parkinson disease (PD) is a common, debilitating neurodegenerative disease characterized by profound slowing of movement (bradykinesia), resting tremor, rigidity, and postural instability. Medical therapy of PD is limited to symptom suppression and has not changed substantially in more than forty years, in part because of limited understanding of the mechanisms responsible for PD-related neurodegeneration. Accumulating evidence from genetic and biochemical studies implicate dysfunction of the endolysosomal pathway as a key feature in PD pathogenesis. Most studies have focused on accumulation of neurotoxic alpha-synuclein secondary to defects in autophagy as the cause of neurodegeneration, but abnormalities of the endolysosomal system likely mediate toxicity through multiple mechanisms. To understand how endolysosomal dysfunction causes PD-related neurodegeneration, I conducted in vivo and cell biological experiments to examine the effects of PD-associated mutations in the genes ATP13A2 and LRRK2 on the endolysosomal system. I generated and characterized a murine model of Kufor-Rakeb syndrome (KRS), a form of early-onset Parkinsonism with additional neurological features caused by recessive loss-of-function mutations in late endosomal/lysosomal protein ATP13A2. I show that Atp13a2 null mice develop age-related motor abnormalities that are preceded by neuropathological changes including gliosis, accumulation of protein aggregates, lipofuscinosis, and lysosomal abnormalities. Contrary to predictions from in vitro data, in vivo mouse genetic studies demonstrate that these phenotypes are alpha-synuclein-independent. These findings indicate that lysosomal dysfunction and abnormalities of alpha-synuclein homeostasis are not synonymous - even in the context of an endolysosomal genetic defect linked to parkinsonism – and highlight the presence of alpha-synuclein-independent neurotoxicity consequent to endolysosomal dysfunction. In addition, I describe a novel interaction between the PD-related protein LRRK2 and microtubules, the main structures responsible for endolysosomal vesicle movement within the cell. Through cell biological studies, I demonstrate that PD-mutant forms of LRRK2 closely associate with microtubules and that loss of LRRK2 kinase activity affects this interaction. As microtubules are necessary for the movement of vesicles within the endolysosomal system, LRRK2 may act as an important signaling molecule on microtubules during vesicular movement. These studies advance our understanding of how PD-related mutations in ATP13A2 and LRRK2 disrupt the endolysosomal system to contribute to PD pathogenesis.

[发布机构] University of Michigan

[效力级别] Science (General)

[关键词] Genetic forms of Parkinson Disease;Science (General);Science;Neuroscience