Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2

Parkinson's disease (PD) is a common neurodegenerative disorder that results from the loss of dopaminergic neurons. Mutations in coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) gene cause a familial form of PD with α‐Synuclein aggregation, and we here identified the pathogenesis of the T61I mutation, the most common disease‐causing mutation of CHCHD2. In Neuro2a cells, CHCHD2 is in mitochondria, whereas the T61I mutant (CHCHD2(T61I)) is mislocalized in the cytosol. CHCHD2(T61l) then recruits casein kinase 1 epsilon/delta (Csnk1e/d), which phosphorylates neurofilament and α‐Synuclein, forming cytosolic aggresomes. In vivo, both Chchd2(T61I) knock‐in and transgenic mice display neurodegenerative phenotypes and aggresomes containing Chchd2(T61I), Csnk1e/d, phospho‐α‐Synuclein, and phospho‐neurofilament in their dopaminergic neurons. Similar aggresomes were observed in a postmortem PD patient brain and dopaminergic neurons generated from patient‐derived iPS cells. Importantly, a Csnk1e/d inhibitor substantially suppressed the phosphorylation of neurofilament and α‐Synuclein. The Csnk1e/d inhibitor also suppressed the cellular damage in CHCHD2(T61I)‐expressing Neuro2a cells and dopaminergic neurons generated from patient‐derived iPS cells and improved the neurodegenerative phenotypes of Chchd2(T61I) mutant mice. These results indicate that Csnk1e/d is involved in the pathogenesis of PD caused by the CHCHD2(T61I) mutation.