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FB2026_01
,
released March 12, 2026
The human GBA1 gene has been identified as a susceptibility locus for the development of Lewy body dementia (see MIM:127750). GBA1 encodes the lysosomal membrane protein glucosylceramidase beta, which is required for glycolipid metabolism. There are two fly orthologs, Gba1a and Gba1b, for which amorphic alleles generated by targeted recombination, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
GBA1 is implicated in several forms of Gaucher disease (see MIM:606463 and FBhh0000227); it has also been identified as a susceptibility locus for the development of late-onset Parkinson disease (MIM:606463, FBhh0000627).
Multiple UAS constructs of the human Hsap\GBA1 gene have been introduced into flies, including wild-type and genes carrying mutations associated with Gaucher disease and Parkinson disease. Heterologous rescue (functional complementation) has been demonstrated for glial-specific knockdown of Gba1b. Variant(s) implicated in human disease tested (as transgenic human gene, GBA1): the L444P (L483P) variant form and the N370S (N409S) variant form have been introduced into flies. Both mutant variants studied are also implicated in Lewy body dementia; see the 'Disease-Implicated Variants' table below.
Animals homozygous for an amorphic allele of Dmel\Gba1b have been used to characterize cellular phenotypes associated with neurodegenerative protein aggregation; changes in the turnover and abundance of proteins associated with extracellular vesicles are observed.
[updated Mar. 2019 by FlyBase; FBrf0222196]
LBD is a chronic, neurodegenerative cognitive disorder; it is the third-most common form of dementia (https://parkinsonsdisease.net/clinical/lewy-body-dementia-differences/).
Because symptoms of Lewy body dementia can closely resemble other more commonly known disorders like Alzheimer disease and Parkinson disease, it is often underdiagnosed or misdiagnosed. In LBD, dementia appears first or around the same time as parkinsonism. In contrast, for dementia associated with Parkinson disease, dementia develops after several or many years of living with Parkinson disease. (https://www.davisphinneyfoundation.org/blog/difference-lewy-body-dementia-parkinsons-disease-alzheimers-disease/)
Dementia with Lewy bodies (DLB) is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication (McKeith et al., 1996, pubmed:8909416; Mizutani, 2000, pubmed:11068444; McKeith et al., 2005, pubmed:16237129). [from MIM:127750; 2019.06.03]
GBA has been identified as a susceptibility locus for Lewy body dementia. [from MIM:127750; 2019.06.03]
The variable locations of Lewy bodies observed in the brain correlate with the different diseases associated with this pathology (Parkinson, Parkinson dementia, and Lewy body dementia) (https://www.apdaparkinson.org/article/understanding-parkinsons-disease-dementia-lewy-bodies/).
At autopsy, SNCA-positive Lewy body protein aggregates are observed within neurons of the brain; Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease. For diagnosis, brainstem or cortical Lewy bodies are the only essential pathologic features. (McKeith et al., 1996, pubmed:8909416; Mizutani, 2000, pubmed:11068444; McKeith et al., 2005, pubmed:16237129) [from MIM:127750; 2019.06.03]
GBA (Glucosylceramidase Beta) encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. [from Gene Cards, GBA; 2017.09.22]
One to many: 1 human to 2 Drosophila.
High-scoring ortholog of human GBA (2 Drosophila to 1 human). Dmel\Gba1b shares 32% identity and 50% similarity with human GBA.