Abstract
Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson’s disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice. Here, we show that GBA1 enzyme activity plays a significant role in the hA53T α-synuclein induced α-synucleinopathy. The expression of D409H GBA1 markedly shortens the lifespan of hA53T α-synuclein transgenic mice. Moreover, D409H GBA1 expression exacerbates the formation of insoluble aggregates of α-synuclein, glial activation, neuronal degeneration, and motor abnormalities in the hA53T α-synuclein transgenic mice. Interestingly, the expression of D409H GBA1 results in the loss of dopaminergic neurons in the substantia nigra pars compacta of hA53T transgenic mice. Taken together, these results indicate that GBA1 deficiency due to D409H mutation affects the disease onset and course in hA53T α-synuclein transgenic mice. Therefore, strategies aimed to maintain GBA1 enzyme activity could be employed to develop an effective novel therapy for GBA1 linked-PD and related α-synucleinopathies.
Highlights
Parkinson’s Disease (PD) is a neurodegenerative disorder that affects approximately 1-2% of the elderly population [33]
glucocerebrosidase 1 (GBA1) enzyme deficiency caused by GBA1 D409H mutation increases the levels of α-synuclein To test our hypothesis that decreased GBA1 enzyme activity due to mutation in GBA1 affects neurodegeneration in the human A53T (hA53T) α-synuclein transgenic (Tg) mouse model of PD, the GBA1D409H/D409H mutant mice [45] were crossbred with the hA53T α-synuclein (α-Syn) Tg mice (Fig. 1)
Our study revealed that phosphoserine 129 α-synuclein immunoreactivity and high molecular weight α-synuclein species were detected in the ventral midbrain of hA53T α-Syn;GBA1+/D409H and hA53T α-Syn;GBA1D409H/D409H mice at 6 months of age
Summary
Parkinson’s Disease (PD) is a neurodegenerative disorder that affects approximately 1-2% of the elderly population [33]. Many pathologically sequestered protein aggregates are found in LBs in which α-synuclein is a dominating component [43]. Homozygous mutations in GBA1 cause a lysosomal storage disorder, Gaucher disease, whereas heterozygous mutations in GBA1 are implicated in PD and DLB [9, 12, 42]. Mutations in GBA1 lead to GBA1 enzyme deficiency and result in α-synuclein accumulation [27, 41]. Clinical pathology of PD, in which GBA1 mutations are present, displayed the presence of a greater number of LBs and LNs [4, 25]. Recent studies have revealed that GBA1 enzyme activity and the steadystate level of wild type GBA1 protein are both reduced in the postmortem of PD patients with and without GBA1 mutations [1, 2, 11, 31, 36], indicating the pivotal role of GBA1 on the development of sporadic PD
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