NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons

Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1)...

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Published in:	Stem cell research Vol. 30; pp. 150 - 162
Main Authors:	Higelin, Julia, Catanese, Alberto, Semelink-Sedlacek, Lena Luisa, Oeztuerk, Sertap, Lutz, Anne-Kathrin, Bausinger, Julia, Barbi, Gotthold, Speit, Günter, Andersen, Peter M., Ludolph, Albert C., Demestre, Maria, Boeckers, Tobias M.
Format:	Journal Article
Language:	English
Published:	England Elsevier B.V 01-07-2018 Elsevier
Subjects:	ALS Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - pathology DNA damage DNA Damage - genetics hiPSC Humans Motor Neurons - metabolism Mutation NEK1 Neurodegeneration NIMA-Related Kinase 1 - genetics Transfection DSB ATM (serine/threonine kinase), BRCA1 DDR CHK1 hiPSC Neurodegeneration DNA damage ALS NEK1 HR NHEJ
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Summary:	Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS. •An ALS-associated NEK1 mutation leads to NEK1 haploinsufficiency in human iPS derived cells.•In neurons -as opposed to stem cells- NEK1 mutations are associated with increased DNA damage and impaired DNA repair.•Compromised DNA damage repair mechanisms in NEK1 mutants lead to increased cell death of motoneurons.•NEK1 mutated motoneurons show a dysregulation of the DDR machinery.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1873-5061 1876-7753 1876-7753
DOI:	10.1016/j.scr.2018.06.005