Abstract
As a pathological hallmark of Parkinson's disease (PD), a-synucleinopathy induces various cellular damages, including calcium overload, mitochondrial and autophagic dysfunction, ultimately resulting in dopaminergic neuron death. However, the hierarchy of these detrimental events remains unclear. It is well established that a-synuclein can induce calcium overload through diverse mechanisms. To assess whether calcium overload plays a crucial detrimental role, we established a calcium overload model in Drosophila and conducted genetic screening. Our findings indicate that calcium overload caused mitochondrial damage and lysosomal dysfunction, leading to cell death, and these cytotoxic processes were significantly mitigated by the loss of Tousled-like kinase (TLK). Notably, the loss of TLK also ameliorated defects induced by a-synuclein overexpression in Drosophila. This suggests that calcium overload is a critical event in a-synucleinopathy. In mammalian cells and mice, calcium overload activated TLK2 (the homologue of Drosophila TLK) by enhancing TLK2 phosphorylation, which increases TLK2 kinase activity. Increased TLK2 phosphorylation was detected in the brains of GluR1[Lc] and a-synuclein overexpression mice, suggesting that TLK2 is activated under these pathological conditions. Furthermore, TLK2 knockout mice exhibited rescue of multi-aspect cytotoxicity induced by calcium overload and a-synuclein overexpression. Our research demonstrates that TLK2 activation by calcium overload appears to be a pivotal step in the progression of PD. This finding provides a potential link between calcium overload, the subsequent mitochondrial and lysosomal dysfunction observed in the disease.
