Exploring the link between glucocerebrosidase mutations and parkinsonism

Abstract

Clinical, genetic and pathological studies all demonstrate that mutations in glucocerebrosidase (GBA), which encodes the lysosomal enzyme deficient in Gaucher disease (GD), are an important and common risk factor for Parkinson disease (PD) and related disorders. Some patients with GD and Gaucher carriers develop parkinsonism. Furthermore, subjects with PD have a greatly increased frequency of GBA mutations. GBA mutation carriers exhibit diverse parkinsonian phenotypes, and have glucocerebrosidase-positive Lewy bodies. Although the mechanism for this association is unknown, we present several theories, including enhanced protein aggregation, prion transmission, lipid accumulation, and impaired autophagy, mitophagy or trafficking. Each has inherent limitations, and an unknown “second hit” might be essential. Elucidating the basis for this link will have important consequences and should provide new insights into lysosomal pathways and potential treatment strategies.

LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance

“…Mutations in GBA1, the gene encoding GC, lead to Gaucher disease (GD), a lysosomal storage disorder that has been linked to Parkinson disease (PD) (10). LIMP-2 has been identified as a modifier for the neurological presentation of GD (11).…”

Novel Activity‐Based Probes for Broad‐Spectrum Profiling of Retaining β‐Exoglucosidases In Situ and In Vivo

“…[1][2][3][4][5][6] Deficiency of GBA1 forms the basis for the most common inherited lysosomal storage disorder, Gaucher disease. [2] Recently, mutations of GBA1 have been reported to markedly increase the risk for Parkinsonism, [7][8][9] and excessive degradation of glucosylceramide by GBA2 may play a role in neuropathology. [4,[10][11][12] The cytosolic broadspecificity b-glucosidase (GBA3) is thought to be involved in degrading xenobiotic b-glucosides.…”

“…Further investigations of GBA1 and GBA2 using ABPs are of particular interest because of the observed link between deficiency in GBA1 and the risk for the development of Parkinsonism. [7][8][9] It is conceivable that impaired degradation of glucosylceramide in GBA-deficient lysosomes is compensated by non-lysosomal hydrolysis by GBA2. [10] GBA2 may thus play an important role in pathophysiological processes associated with GBA1 deficiency.…”

Cognitive and Antipsychotic Medication Use in Monoallelic GBA-Related Parkinson Disease

“…This effect is postulated to result from reduction in residual lysosomal function. Because monoallelic GBA mutations may disturb lysosomal dysfunction (Westbroek et al 2011), there is a parallel concern for GBA-PD. As cationic amphiphilic drugs, both quetiapine and clozapine tend to accumulate in lysosomes and can interfere with lysosomal function and autophagy (Anderson and Borlak 2006).…”