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 pathogenesi...

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Published in:	EMBO molecular medicine Vol. 15; no. 9; p. e17451
Main Authors:	Torii, Satoru, Arakawa, Satoko, Sato, Shigeto, Ishikawa, Kei‐ichi, Taniguchi, Daisuke, Sakurai, Hajime Tajima, Honda, Shinya, Hiraoka, Yuuichi, Ono, Masaya, Akamatsu, Wado, Hattori, Nobutaka, Shimizu, Shigeomi
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 11-09-2023 EMBO Press John Wiley and Sons Inc Springer Nature
Subjects:	Aggresomes Alzheimer's disease Apoptosis Biomedicine Casein Casein kinase I CHCHD2 Csnk1e/d Cytosol Dementia Dopamine receptors EMBO16 EMBO24 EMBO27 Kinases Localization Mitochondria Molecular Medicine Movement disorders Mutants Mutation Neurodegenerative diseases Neurogenesis Neurons Parkinson's disease Pathogenesis Patients Phenotypes Phosphorylation Plasmids Proteins Synuclein Transgenic mice α‐Synuclein CHCHD2 Csnk1e/d α‐Synuclein α-Synuclein
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Summary:	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. Synopsis Parkinson's disease (PD) is the second most common neurodegenerative disorder. The Thr61Ile (T61I) mutation of coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2/PARK22) is a causative factor for familial PD. However, the pathogenesis of this mutation in PD remains unclear. Mutant CHCHD2 T61I was mislocalized to the cytoplasm in Neuro2a cells, where Casein kinase 1 epsilon and delta (Csnk1e/d) were accumulated. Neurofilament and α‐Synuclein were phosphorylated by Csnk1e/d, resulting in the formation of aggresomes in dopaminergic neurons expressing CHCHD2 T61l . Accumulated Chchd2 with Csnk1e/d and p‐α‐Synuclein, and dopaminergic neuronal loss were found in Chchd2 T61I knock‐in mice. Similar abnormalities were found in the postmortem brain of a CHCHD2 T61I PD patient and iPSC‐derived dopaminergic neurons with the CHCHD2 T61I mutation. The neurodegenerative phenotypes and neuronal pathology of Chchd2 T61I mutant mice and cellular damage in iPSC‐derived dopaminergic neurons with the CHCHD2 T61I mutation were improved by pharmacological inhibition of Csnk1e/d. Graphical Abstract Parkinson's disease (PD) is the second most common neurodegenerative disorder. The Thr61Ile (T61I) mutation of coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2/PARK22) is a causative factor for familial PD. However, the pathogenesis of this mutation in PD remains unclear.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1757-4676 1757-4684
DOI:	10.15252/emmm.202317451