Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration.
Mutations in the glucosidase, beta, acid (GBA1) gene cause Gaucher's disease, and are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) excluding variants of low penetrance. Because α-synuclein-containing neuronal aggregates are a defining...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-03-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4809718?pdf=render |
| _version_ | 1811227972005265408 |
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| author | Marie Y Davis Kien Trinh Ruth E Thomas Selina Yu Alexandre A Germanos Brittany N Whitley Sergio Pablo Sardi Thomas J Montine Leo J Pallanck |
| author_facet | Marie Y Davis Kien Trinh Ruth E Thomas Selina Yu Alexandre A Germanos Brittany N Whitley Sergio Pablo Sardi Thomas J Montine Leo J Pallanck |
| author_sort | Marie Y Davis |
| collection | DOAJ |
| description | Mutations in the glucosidase, beta, acid (GBA1) gene cause Gaucher's disease, and are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) excluding variants of low penetrance. Because α-synuclein-containing neuronal aggregates are a defining feature of PD and DLB, it is widely believed that mutations in GBA1 act by enhancing α-synuclein toxicity. To explore this hypothesis, we deleted the Drosophila GBA1 homolog, dGBA1b, and compared the phenotypes of dGBA1b mutants in the presence and absence of α-synuclein expression. Homozygous dGBA1b mutants exhibit shortened lifespan, locomotor and memory deficits, neurodegeneration, and dramatically increased accumulation of ubiquitinated protein aggregates that are normally degraded through an autophagic mechanism. Ectopic expression of human α-synuclein in dGBA1b mutants resulted in a mild enhancement of dopaminergic neuron loss and increased α-synuclein aggregation relative to controls. However, α-synuclein expression did not substantially enhance other dGBA1b mutant phenotypes. Our findings indicate that dGBA1b plays an important role in the metabolism of protein aggregates, but that the deleterious consequences of mutations in dGBA1b are largely independent of α-synuclein. Future work with dGBA1b mutants should reveal the mechanism by which mutations in dGBA1b lead to accumulation of protein aggregates, and the potential influence of this protein aggregation on neuronal integrity. |
| first_indexed | 2024-04-12T09:50:40Z |
| format | Article |
| id | doaj.art-3fb37e6949374aa09f6955f77c9a395e |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T09:50:40Z |
| publishDate | 2016-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-3fb37e6949374aa09f6955f77c9a395e2022-12-22T03:37:50ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-03-01123e100594410.1371/journal.pgen.1005944Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration.Marie Y DavisKien TrinhRuth E ThomasSelina YuAlexandre A GermanosBrittany N WhitleySergio Pablo SardiThomas J MontineLeo J PallanckMutations in the glucosidase, beta, acid (GBA1) gene cause Gaucher's disease, and are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) excluding variants of low penetrance. Because α-synuclein-containing neuronal aggregates are a defining feature of PD and DLB, it is widely believed that mutations in GBA1 act by enhancing α-synuclein toxicity. To explore this hypothesis, we deleted the Drosophila GBA1 homolog, dGBA1b, and compared the phenotypes of dGBA1b mutants in the presence and absence of α-synuclein expression. Homozygous dGBA1b mutants exhibit shortened lifespan, locomotor and memory deficits, neurodegeneration, and dramatically increased accumulation of ubiquitinated protein aggregates that are normally degraded through an autophagic mechanism. Ectopic expression of human α-synuclein in dGBA1b mutants resulted in a mild enhancement of dopaminergic neuron loss and increased α-synuclein aggregation relative to controls. However, α-synuclein expression did not substantially enhance other dGBA1b mutant phenotypes. Our findings indicate that dGBA1b plays an important role in the metabolism of protein aggregates, but that the deleterious consequences of mutations in dGBA1b are largely independent of α-synuclein. Future work with dGBA1b mutants should reveal the mechanism by which mutations in dGBA1b lead to accumulation of protein aggregates, and the potential influence of this protein aggregation on neuronal integrity.http://europepmc.org/articles/PMC4809718?pdf=render |
| spellingShingle | Marie Y Davis Kien Trinh Ruth E Thomas Selina Yu Alexandre A Germanos Brittany N Whitley Sergio Pablo Sardi Thomas J Montine Leo J Pallanck Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration. PLoS Genetics |
| title | Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration. |
| title_full | Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration. |
| title_fullStr | Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration. |
| title_full_unstemmed | Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration. |
| title_short | Glucocerebrosidase Deficiency in Drosophila Results in α-Synuclein-Independent Protein Aggregation and Neurodegeneration. |
| title_sort | glucocerebrosidase deficiency in drosophila results in α synuclein independent protein aggregation and neurodegeneration |
| url | http://europepmc.org/articles/PMC4809718?pdf=render |
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