Abstract
Lysosomal dysfunction is a central pathway associated with Parkinson’s disease (PD) pathogenesis. Haploinsufficiency of the lysosomal hydrolase GBA (encoding glucocerebrosidase (GCase)) is one of the largest genetic risk factors for developing PD. Deficiencies in the activity of the GCase enzyme have been observed in human tissues from both genetic (harboring mutations in the GBA gene) and idiopathic forms of the disease. To understand the mechanisms behind the deficits of lysosomal GCase enzyme activity in idiopathic PD, this study utilized a large cohort of fibroblast cells from control subjects and PD patients with and without mutations in the GBA gene (N370S mutation) (control, n = 15; idiopathic PD, n = 31; PD with GBA N370S mutation, n = 6). The current data demonstrates that idiopathic PD fibroblasts devoid of any mutations in the GBA gene also exhibit reduction in lysosomal GCase activity, similar to those with the GBA N370S mutation. This reduced GCase enzyme activity in idiopathic PD cells was accompanied by decreased expression of the GBA trafficking receptor, LIMP2, and increased ER retention of the GBA protein in these cells. Importantly, in idiopathic PD fibroblasts LIMP2 protein levels correlated significantly with GCase activity, which was not the case in control subjects or in genetic PD GBA N370S cells. In conclusion, idiopathic PD fibroblasts have decreased GCase activity primarily driven by altered LIMP2-mediated transport of GBA to lysosome and the reduced GCase activity exhibited by the genetic GBA N370S derived PD fibroblasts occurs through a different mechanism.
Highlights
Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder, and several cell biological pathways that contribute to PD etiology have been described, including mitochondrial dysfunction, oxidative stress, lysosomal dysfunction, lipid and lipid transport abnormalities, vesicular transport deficits, immune response activation, and protein aggregation pathways [1,2,3]
Idiopathic PD patient fibroblasts display reduced basal GCase activity compared to healthy subject controls Our previous findings demonstrated that GCase activity progressively declines with age, and is decreased in PD patient substantia nigra compared to healthy patients [4]
To exclude the possibility of altered lysosomal load contributing to the reduced lysosomal GCase activity in PD fibroblasts, an immunoblot assay was performed for LAMP1, and no change in its expression was observed between the PD-derived cells compared to healthy subject controls (HS) controls (Additional file 1: Fig. S1A, B, Additional file 2)
Summary
Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder, and several cell biological pathways that contribute to PD etiology have been described, including mitochondrial dysfunction, oxidative stress, lysosomal dysfunction, lipid and lipid transport abnormalities, vesicular transport deficits, immune response activation, and protein aggregation pathways [1,2,3]. Glucocerebrosidase (GCase), a lysosomal hydrolase encoded by the GBA gene, is responsible for the metabolism of the glycosphingolipid substrates glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). While homozygous mutations in this gene lead to the most prevalent lysosomal storage disorder Gaucher’s disease, heterozygous loss-of-function mutations in GBA are one of the Thomas et al Mol Brain (2021) 14:16 most common genetic risk factors identified in PD [5,6,7]. Some studies have postulated a potential interaction between GBA and alpha-synuclein whereby accumulation of the substrates GlcCer and GlcSph, dysfunction of autophagy and ubiquitin proteasome system observed in models with mutant GBA was associated with increased accumulation of alpha-synuclein, and increased level of alpha-synuclein result in reduced GCase activity [12, 20]
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