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.

Keywords: Animal models; Glucocerebrosidase; LRRK2; Lysosomes; Neuropathology; Parkinson’s disease.

Fig. 1

Interactions of LRRK2 and GCase in lysosome function. LRRK2 modulates lysosome function, probably through regulation of Ca²⁺ release from this store. Lysosomal Ca²⁺ exits in the cytosol through TPC2 channels, whose efficacy is altered by LRRK2 mutations. Glucocerebrosidase (GCase) is trafficked into the lysosomal lumen where it is activated by the acidic pH. LRRK2 is capable of modulating GCase activity, but the exact molecular mechanism is yet to be elucidated, as no indications exist whether LRRK2 might be present inside the lysosome. LRRK2 might directly affect GCase activity (a); or it could alter lysosome function, with downstream consequences on GCase biology, such as activity, trafficking or expression (b); LRRK2-dependent regulation of lysosomal TPC2 channels could also lead to alterations in GCase functionality as a secondary consequence (c)

Fig. 2

Main features of LRRK2 and GBA1 knock-in mice. Mice carrying PD-related mutations in the endogenous Lrrk2 gene do not display neurodegeneration or neuropathology, but show alterations in neuronal and synaptic function reminiscent of early-stage PD. This is generally accompanied by changes in motor and cognitive abilities, with reports of age-dependency of these phenotypes. Similarly, KI mice with GBA1 mutations do not show neuronal loss and generally only mild accumulation of aSyn. Molecularly, they correctly present reduction of GCase enzymatic activity in several tissues, but behavioral phenotypes have been scarcely investigated. Of note, constitutive GCase loss of function is neonatally lethal in mice

Fig. 3

Proposed future in vivo studies in LRRK2 and GBA1 models. To advance our understanding of the functions of LRRK2 and GCase in the living brain, different experimental paradigms could be performed. To assess the synaptic roles of lysosome, and how LRRK2 and GCase might converge in this process, animal models can be utilized for electrophysiology in acute brain slices to measure neuronal and synaptic transmission in relevant brain areas (such as the striatum, depicted). The combination of LRRK2 and GBA1 manipulation could be performed to probe their functional interactions, using viral delivery approaches or crossing different models (with a special usefulness of conditional manipulations allowing temporal and spatial control). The biological connection between lysosomes and synapses could be explored with more accuracy exploiting the great advances in optogenetic control of both neuronal transmission and lysosome acidification. Lastly, lysosome function could be modulated pharmacologically in LRRK2, GBA1 and dual LRRK2-GBA1 animal models to acutely dissect the lysosomal contribution to phenotypes