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Increased Levels of the Parkinson's Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of α-Synuclein, Independent of Mutation Status.


ABSTRACT: Autosomal dominant mutations in the gene encoding α-synuclein (SNCA) were the first to be linked with hereditary Parkinson's disease (PD). Duplication and triplication of SNCA has been observed in PD patients, together with mutations at the N-terminal of the protein, among which A30P and A53T influence the formation of fibrils. By overexpressing human α-synuclein in the neuronal system of Drosophila, we functionally validated the ability of IP3K2, an ortholog of the GWAS identified risk gene, Inositol-trisphosphate 3-kinase B (ITPKB), to modulate α-synuclein toxicity in vivo. ITPKB mRNA and protein levels were also increased in SK-N-SH cells overexpressing wild-type α-synuclein, A53T or A30P mutants. Kinase overexpression was detected in the cytoplasmatic and in the nuclear compartments in all α-synuclein cell types. By quantifying mRNAs in the cortex of PD patients, we observed higher levels of ITPKB mRNA when SNCA was expressed more (p < 0.05), compared to controls. A positive correlation was also observed between SNCA and ITPKB expression in the cortex of patients, which was not seen in the controls. We replicated this observation in a public dataset. Our data, generated in SK-N-SH cells and in cortex from PD patients, show that the expression of α-synuclein and ITPKB is correlated in pathological situations.

SUBMITTER: Di Leva F 

PROVIDER: S-EPMC9916293 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Increased Levels of the Parkinson's Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of α-Synuclein, Independent of Mutation Status.

Di Leva Francesca F   Filosi Michele M   Oyston Lisa L   Silvestri Erica E   Picard Anne A   Lavdas Alexandros A AA   Lobbestael Evy E   Baekelandt Veerle V   Neely G Gregory GG   Pramstaller Peter P PP   Hicks Andrew A AA   Corti Corrado C  

International journal of molecular sciences 20230119 3


Autosomal dominant mutations in the gene encoding α-synuclein (<i>SNCA</i>) were the first to be linked with hereditary Parkinson's disease (PD). Duplication and triplication of <i>SNCA</i> has been observed in PD patients, together with mutations at the N-terminal of the protein, among which A30P and A53T influence the formation of fibrils. By overexpressing human α-synuclein in the neuronal system of <i>Drosophila</i>, we functionally validated the ability of <i>IP3K2</i>, an ortholog of the G  ...[more]

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