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• W4285802106 abstract "Abstract As a pathological hallmark in Parkinson’s disease (PD), α-synucleinopathy causes multiple cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, and eventually dopamine neuron death. However, the hierarchy of these detrimental events is unclear. In Drosophila , we confirmed that overexpression of α-synuclein could induce all these cytotoxic events. To determine the specific cytotoxic events induced by calcium overload, we established a calcium overload model in Drosophila and performed genetic screens. We found that calcium overload caused mitochondrial damage and autophagy failure and cell death, and these cytotoxic processes could be strongly rescued by loss of Tousled-like kinase (TLK). Interestingly, loss of TLK also rescued defects induced by α-synuclein overexpression in Drosophila . This suggests that calcium overload acts as the crucial event upstream of mitochondrial and autophagy dysfunction. For TLK regulation of autophagy, our data indicated that a transcriptional factor REPTOR, which regulated the expression of several lysosomal genes, functioned downstream of TLK. In mammalian cells and mice, TLK2 (the homolog of Drosophila TLK) was phosphorylated under calcium overload. Upon phosphorylation, TLK2 increased its kinase activity. In addition, TLK2 could phosphorylate CREBRF (the human homolog of REPTOR) to cause its loss of transcription on the lysosomal genes. Moreover, TLK2 knockout mice rescued multi-aspect cytotoxicity induced by calcium overload and α-synuclein overexpression. Our research demonstrates that TLK2 acts as a key regulator to mediate cell death and dysfunctions of mitochondria and autophagy downstream of calcium overload." @default.
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• W4285802106 date "2022-07-18" @default.
• W4285802106 modified "2023-09-24" @default.
• W4285802106 title "α-synucleinopathy associated calcium overload and autophagy failure is regulated by gain-of-function of Tousled-like kinase" @default.
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• W4285802106 doi "https://doi.org/10.1101/2022.07.17.500360" @default.
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