Lysosomal Pathogenesis of Parkinson's Disease: Insights From LRRK2 and GBA1 Rodent Models

Abstract

The discovery of mutations in LRRK2 and GBA1 that are linked to Parkinson’s disease provided further evidence that autophagy and lysosome pathways are likely implicated in the pathogenic process. Their protein products are important regulators of lysosome function. LRRK2 has kinase-dependent effects on lysosome activity, autophagic efficacy and lysosomal Ca2+ signaling. Glucocerebrosidase (encoded by GBA1) is a hydrolytic enzyme contained in the lysosomes and contributes to the degradation of alpha-synuclein. PD-related mutations in LRRK2 and GBA1 slow the degradation of alpha-synuclein, thus directly implicating the dysfunction of the process in the neuropathology of Parkinson’s disease. The development of genetic rodent models of LRRK2 and GBA1 provided hopes of obtaining reliable preclinical models in which to study pathogenic processes and perform drug validation studies. Here, I will review the extensive characterization of these models, their impact on understanding lysosome alterations in the course of Parkinson’s disease and what novel insights have been obtained. In addition, I will discuss how these models fare with respect to the features of a “gold standard” animal models and what could be attempted in future studies to exploit LRRK2 and GBA1 rodent models in the fight against Parkinson’s disease.

A New Look at Animal Models of Neurological Disorders

“…Besides alpha-synuclein, other proteins became a focus of intense interest in the animal model field because of their association, through human genetic studies, with neurological disorders that are rarely familial and much more often sporadic, such as Parkinson's disease [9] and frontotemporal dementia [10]. In both cases, genetic manipulations in mice attempt to provide insights into the human disease by reproducing the mutation to study its effects on the mammalian brain, in order to hopefully identify novel therapeutic targets, as explained by Volta [9] and by Kashyap et al [10], respectively, in their contributions. Similarly, new mechanistic data on the frequent neurological disorder Restless Leg Syndrome have led to efforts to generate and evaluate novel models of the disorder as reviewed by Silvani and colleagues [11].…”