Glucocerebrosidase dysfunction in neurodegenerative disease

Abstract

Parkinson’s disease (PD) and related neurodegenerative disorders, termed the synucleinopathies, are characterized pathologically by the accumulation of protein aggregates containing α-synuclein (aSyn), resulting in progressive neuronal loss. There is considerable need for the development of neuroprotective strategies to halt or slow disease progression in these disorders. To this end, evaluation of genetic mutations associated with the synucleinopathies has helped to elucidate crucial mechanisms of disease pathogenesis, revealing key roles for lysosomal and mitochondrial dysfunction. The GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase) is the most common genetic risk factor for PD and is also linked to other neurodegenerative disorders including dementia with Lewy bodies (DLB). Additionally, homozygous mutations in GBA1 are associated with the rare lysosomal storage disorder, Gaucher’s disease (GD). In this review, we discuss the current knowledge in the field regarding the diverse roles of GCase in neurons and the multifactorial effects of loss of GCase enzymatic activity. Importantly, GCase has been shown to have a bidirectional relationship with aSyn, resulting in a pathogenic feedback loop that can lead to progressive aSyn accumulation. Alterations in GCase activity have furthermore been linked to multiple distinct pathways involved in neurodegeneration, and therefore GCase has emerged as a promising target for therapeutic drug development for PD and related neurodegenerative disorders, particularly DLB.

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

“…Notably, deficiency in glucosylceramidase beta 1 (GBA1) and cyclin G associated kinase (GAK) are established as genetic risk factors in 5–10% of cases of PD ( Latourelle et al, 2009 ; Tysnes and Storstein, 2017 ; Avenali et al, 2020 ; Miyazaki et al, 2021 ). GBA1 deficiency specifically reduces lysosome function, leading to autophagy inhibition ( Schöndorf et al, 2014 ; Brooker and Krainc, 2021 ; Kuo et al, 2022 ). GBA1 is required for ALR, and its deficiency leads to impaired lysosome homeostasis ( Awad et al, 2015 ; Magalhaes et al, 2016 ).…”

Autophagic lysosome reformation in health and disease

“…Genetic risk factors are identified in approximately 5–10% of cases of PD [ 88 ], and associated genes include GBA1 (glucosylceramidase beta 1) and GAK (cyclin G associated kinase) [ 63–65 ], which are required for ALR [ 54 , 66 ]. GBA1 deficiency leads to reduced lysosome function [ 90 ] and autophagy inhibition [ 91 , 92 ] that correlates with neurodegeneration [ 93 ]. GBA1 deficiency also results in an inability to maintain lysosome homeostasis [ 54 , 94 ], that has been attributed to reduced activation of MITF/TFEB-dependent de novo lysosome biogenesis [ 94 ], but GBA1 is also required for ALR [ 54 ].…”

Challenges in Rare Diseases Diagnostics: Incontinentia Pigmenti with Heterozygous GBA Mutation

“…The underlying causes of all forms of GD are the homozygous or compound heterozygous mutations in the GBA gene, resulting in a lysosomal deficiency of glucocerebrosidase activity with a broad spectrum of phenotypes [ 14 ]. These mutations can also contribute to neurodegeneration [ 15 ]. GD has an estimated prevalence of 1.3/100,000 [ 4 ].…”