The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA

Abstract

GBA gene variants were the first genetic risk factor for Parkinson’s disease. GBA encodes the lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. GBA exhibits a complex physiological function that includes not only the degradation of its substrate glucosylceramide but also the metabolism of other sphingolipids and additional lipids such as cholesterol, particularly when glucocerebrosidase activity is deficient. In the context of Parkinson’s disease associated with GBA, the loss of GBA activity has been associated with the accumulation of α-synuclein species. In recent years, several hypotheses have proposed alternative and complementary pathological mechanisms to explain why lysosomal enzyme mutations lead to α-synuclein accumulation and become important risk factors in Parkinson’s disease etiology. Classically, loss of GBA activity has been linked to a dysfunctional autophagy–lysosome system and to a subsequent decrease in autophagy-dependent α-synuclein turnover; however, several other pathological mechanisms underlying GBA-associated parkinsonism have been proposed. This review summarizes and discusses the different hypotheses with a special focus on autophagy-dependent mechanisms, as well as autophagy-independent mechanisms, where the role of other players such as sphingolipids, cholesterol and other GBA-related proteins make important contributions to Parkinson’s disease pathogenesis.

Autophagy‐associated non‐coding RNAs: Unraveling their impact on Parkinson's disease pathogenesis

“…In GBA1-related PD, impaired lysosomal clearance of autophagic substrates and aggregate-prone proteins is linked to decreased GBA activity and the buildup of α-syn species. 32 S-nitrosylation of the autophagic adaptor protein p62 inhibits autophagic flux, leading to the intracellular accumulation of misfolded proteins. This accumulation may contribute to the spread of aggregated α-syn in PD and LB dementia.…”

“…Variants in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GBA), have been associated with a malfunctioning autophagy‐lysosome system and a subsequent reduction in autophagy‐mediated turnover of α‐syn, representing significant risk factors in PD development. In GBA1‐related PD, impaired lysosomal clearance of autophagic substrates and aggregate‐prone proteins is linked to decreased GBA activity and the buildup of α‐syn species 32 . S‐nitrosylation of the autophagic adaptor protein p62 inhibits autophagic flux, leading to the intracellular accumulation of misfolded proteins.…”

Selective dopaminergic vulnerability in Parkinson’s disease: new insights into the role of DAT

“…GBA encodes the lysosomal enzyme glucocerebrosidase, which is involved in the breakdown of glucosylceramide. Reduced glucocerebrosidase activity is associated with impaired lysosomal function and α-synuclein accumulation ( Pang et al, 2022 ; Pradas and Martinez-Vicente, 2023 ).…”

“…Many genes and genetic loci are now linked to the risk for PD using modern genetic methods. Many studies suggest that ALP might be involved in sporadic PD ( Orenstein et al, 2013 ; Zavodszky et al, 2014 ; Ysselstein et al, 2019 ; Cui et al, 2021 ; Pang et al, 2022 ; Shrivastava et al, 2022 ; Pradas and Martinez-Vicente, 2023 ). A recent meta-analysis of genome-wide association studies (GWAS), interrogating data from >13,000 PD patients and > 95,000 controls, identified 26 genetic loci across the genome associated with PD.…”

“…A recent meta-analysis of genome-wide association studies (GWAS), interrogating data from >13,000 PD patients and > 95,000 controls, identified 26 genetic loci across the genome associated with PD. Intriguingly, 16 out of these 26 genetic loci have 18 genes nearby that modulate ALP, namely SYT11 ( Bento et al, 2016 ), RAB7L1 ( Kuwahara et al, 2016 ; Pradhan et al, 2018 ; Shrivastava et al, 2022 ), NUCKS1 ( Zhao et al, 2020 ), GBA ( Murphy and Halliday, 2014 ; Pang et al, 2022 ; Pradas and Martinez-Vicente, 2023 ), SIPA1L2 ( Andres-Alonso et al, 2019 ), TMEM163 ( Cuajungco et al, 2014 ; Cuajungco and Kiselyov, 2017 ), STK39 ( Gallolu Kankanamalage et al, 2016 , 2017 ; He et al, 2022 ), LAMP3 ( Tanaka et al, 2022 ), TMEM175 ( Jinn et al, 2017 ; Hu et al, 2022 ), GAK ( Miyazaki et al, 2021 ; Munson et al, 2021 ), SCARB2 ( Velayati et al, 2011 ), GPNMB ( Robinet et al, 2021 ; Zhu et al, 2022 ), VPS13C ( Cai et al, 2022 ; Hancock-Cerutti et al, 2022 ), RIT2 ( Obergasteiger et al, 2023 ), DDRGK1 ( Cao et al, 2021 ), SNCA ( Sampaio-Marques et al, 2012 ; Song et al, 2014 ), LRRK2 ( Gómez-Suaga and Hilfiker, 2012 ; Orenstein et al, 2013 ; Ysselstein et al, 2019 ), and MAPT ( Zhu et al, 2017 ; Feng et al, 2020 ).…”