Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients

Bennett, Craig L.; Dastidar, Somasish Ghosh; Ling, Shuo-Chien; Malik, Bilal; Ashe, Travis D.; Wadhwa, Mandheer; Miller, Derek B.; Lee, Chang-Woo; Mitchell, Matthew B.; Es, Michael A. van; Grunseich, Christopher; Chen, Yingzhang; Sopher, Bryce L.; Greensmith, Linda; Cleveland, Don W.; Spada, Albert R. La

doi:10.1007/s00401-018-1852-9

Cited by 49 publications

(52 citation statements)

References 70 publications

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“…RanGap1 is normally present around the nuclear membrane (Fig. 5h–i) but is diffused into the nucleus and at times to the cytoplasm [5, 54] (Fig. 5j–k).…”

Section: Resultsmentioning

confidence: 99%

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.

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“…RanGap1 is normally present around the nuclear membrane (Fig. 5h–i) but is diffused into the nucleus and at times to the cytoplasm [5, 54] (Fig. 5j–k).…”

Section: Resultsmentioning

confidence: 99%

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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“…SCAN2 clinical manifestations include progressive cerebellar atrophy, ataxia, and sensorimotor peripheral neuropathy [169][170][171][172][173]. In contrast, ALS4 mainly affects the motor neurons and the spinal cord, leading to muscle dysfunction [174][175][176].…”

Section: Senataxin Spinocerebellar Ataxia With Axonal Neuropathymentioning

confidence: 99%

Protective Mechanisms Against DNA Replication Stress in the Nervous System

Charlier

Martins

2020

Genes

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The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

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“…In another study, cytosolic mislocalization of the transactive response DNAbinding protein (TDP-43) was observed in spinal cord motor neurons in postmortem tissues from all the ALS4 patients examined [8]. TDP-43 is an RNA metabolism factor and is a well-documented biomarker that forms toxic protein aggregates in multiple neurodegenerative diseases including ALS [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…TDP-43 is an RNA metabolism factor and is a well-documented biomarker that forms toxic protein aggregates in multiple neurodegenerative diseases including ALS [9,10]. Recapitulation of TDP-43 histopathology in motor neurons of mice carrying ALS4 mutations led the authors to imply that dysfunction of SETX converges on TDP-43 pathology causing an ALStype motor neurodegeneration [8], although the mechanism was not identified.…”

Section: Introductionmentioning

confidence: 99%

Senataxin: A Putative RNA: DNA Helicase Mutated in ALS4—Emerging Mechanisms of Genome Stability in Motor Neurons

Dutta¹,

Hromas²,

Sung³

2020

Amyotrophic Lateral Sclerosis - Recent Advances and Therapeutic Challenges

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Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, autosomal dominant childhood-or adolescent-onset motor neuron disease caused by genetic defects in senataxin (SETX), a putative RNA-DNA helicase. Studies on the yeast SETX ortholog Sen1 revealed its role in small RNA termination pathways. It has been postulated that ALS4-associated neuronal pathologies could stem from defects in RNA metabolism and altered gene expression. Importantly, SETX prevents the accumulation of R-loops, which are potentially pathogenic RNA-DNA hybrids that stem from perturbations in transcription. SETX also interacts with the tumor suppressor BRCA1 that helps promote DNA double-strand break repair by homologous recombination. As such, SETX could contribute toward the removal of harmful R-loops and DSBs in postmitotic neurons. This chapter will visit the plausible mechanistic role of SETX in R-loop removal and DNA break repair that could prevent the activation of apoptotic cell death in neurons and pathological manifestation of ALS4.

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Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients

Cited by 49 publications

References 70 publications

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Protective Mechanisms Against DNA Replication Stress in the Nervous System

Senataxin: A Putative RNA: DNA Helicase Mutated in ALS4—Emerging Mechanisms of Genome Stability in Motor Neurons

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