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

Higelin, Julia; Catanese, Alberto; Semelink-Sedlacek, Lena Luisa; Oeztuerk, Sertap; Lutz, Anne-Kathrin; Bausinger, Julia; Barbi, Gotthold; Speit, Güenter; Andersen, Peter M.; Ludolph, Albert C.; Demestre, Maria; Boeckers, Tobias M.

doi:10.1016/j.scr.2018.06.005

Cited by 60 publications

(82 citation statements)

References 38 publications

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“…Additionally, it is worth mentioning that Nguyen et al [45] conducted a cohort study and characterized the genetic viability of NEK1 in ALS and frontotemporal dementia ALS (FTD-ALS) patients. Finally, it was demonstrated that the DNA damage accumulation was activated by variants of NEK1 in motoneurons derived from patients [46]. Other ALS-genes were also related to DDR mechanisms, such as FUS1 and C9orf72, which supports the idea that NEK1 plays a role in ALS, since it was also demonstrated to be involved in the DDR.…”

Section: Nek1mentioning

confidence: 56%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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Section: Nek1mentioning

confidence: 56%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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“…Loss of function due to mislocalization results in a loss of VPS4B repression leading to an increased interaction with the ALS-linked protein Charged Multivesicular Body Protein 2B (CHMP2B) thereby disrupting dendritic recycling-endosome trafficking and reducing ALS-linked ERB-B2 Receptor Tyrosine Kinase 4 (ERBB4) surface expression [191][192][193]. Another nuclear role for TDP-43 is in its response to genomic double stranded breaks (DSBs) which accumulate in ALS patients [163,[194][195][196][197][198][199][200]. Mislocalization of TDP-43 through an ALS-causing mutation impair the nuclear localization of DSB-repair proteins and result in the accumulation of DNA damage promoting cell death [163,194,201,202].…”

Section: The Contribution Of Tdp-43 Mislocalization To Cellular Toxicmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

224

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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“…Patients and controls gave their written informed consent prior to skin biopsy. The generation and expansion of iPSC lines from healthy control and familiar ALS patients with defined mutations in the FUS or TDP43 gene and HREs in C9ORF72 (table 1) was recently described (5,11,17,(53)(54)(55). Isogenic C9-KO and C9-GC lines from parental C9 (table 1) were generated by CRISPR-Cas9n-mediated gene-editing and fully characterized in the Sterneckert laboratory (32).…”

Section: Mfcsmentioning

confidence: 99%

High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Kretner

Abo-Rady

et al. 2020

Preprint

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Single sentence summaryPathogenesis in C9ORF72 ALS shows a distinct spatiotemporal axonal organelle trafficking impairment caused by gain and loss of function mechanisms. AbstractIntronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS), a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOF) through DPRs versus loss of C9ORF72 functions (LOF). Through multiparametric HC live profiling in spinal MNs from induced pluripotent stem cells (iPSCs)and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA strand breaks (DSBs), DPRs and apoptosis. We show that both GOF and LOF were necessary to yield the overall C9ORF72 pathology.Finally, C9ORF72 LOF was sufficientalbeit to a smaller extentto induce proximal axonal trafficking deficits and increased DSBs.

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

Cited by 60 publications

References 38 publications

Checking NEKs: Overcoming a Bottleneck in Human Diseases

Checking NEKs: Overcoming a Bottleneck in Human Diseases

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

High content live profiling reveals concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

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