Late-onset and selective death of motor neurons in transgenic mice overexpressing peripherin

Peripherin, a type III intermediate filament (IF) protein, upregulated by injury and inflammatory cytokines, is a component of IF inclusion bodies associated with degenerating motor neurons in sporadic amyotrophic lateral sclerosis (ALS). We report here that sustained overexpression of wild-type peripherin in mice provokes massive and selective degeneration of motor axons during aging. Remarkably, the onset of peripherin-mediated disease was precipitated by a deficiency of neurofilament light (NF-L) protein, a phenomenon associated with sporadic ALS. In NF-L null mice, the overexpression of peripherin led to early- onset formation of IF inclusions and to the selective death of spinal motor neurons at 6 mo of age. We also report the formation of similar peripherin inclusions in presymptomatic transgenic mice expressing a mutant form of superoxide dismutase linked to ALS. Taken together, these results suggest that IF inclusions containing peripherin may play a contributory role in motor neuron disease.

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Otolaryngologist’s role in the diagnosis of amyotrophic lateral sclerosis

BMJ Case Reports ◽

10.1136/bcr-2020-234504 ◽

2021 ◽

Vol 14 (2) ◽

pp. e234504

Author(s):

Joana Borges Costa ◽

Diogo Pereira ◽

Delfim Duarte ◽

Miguel Viana

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Clinical Presentation ◽

Late Onset ◽

History Of ◽

Dysarthric Speech ◽

Selective Death ◽

Hypernasal Voice ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and late-onset fatal neurodegenerative disease characterised by selective death of motor neurons. The aetiology of ALS is still unknown and it is extremely heterogeneous in genetics and clinical presentation, being the respiratory failure the usual cause of death. We describe a case of a 61-year-old male patient referred to the otolaryngology consultation for a 6-month history of progressive solid dysphagia and dysphonia. The patient presented several voice alterations such as a dysarthric speech with hypernasal voice which evoked the hypothesis of a neuromuscular disease. That patient was observed by a neurologist and was submitted to an electromyography that confirmed the ALS diagnosis. This case highlights the key role of otolaryngologists in the diagnosis of ALS, in a way that many patients with a bulbar ALS form are initially studied by an otolaryngologist.

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A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis

Biochemistry and Cell Biology ◽

10.1139/o95-064 ◽

1995 ◽

Vol 73 (9-10) ◽

pp. 593-597 ◽

Cited By ~ 31

Author(s):

Jean-Pierre Julien

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Transgenic Mice ◽

Axonal Transport ◽

Motor Neurons ◽

Intracellular Transport ◽

Late Onset ◽

Cytoskeletal Proteins ◽

H Gene ◽

Abnormal Accumulation ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of motor neurons, characterized by abnormal accumulation of neurofilaments (NFs) in perikarya and proximal axons. Two lines of evidence suggest that neurofilament accumulation can play a crucial role in ALS pathogenesis. First, transgenic mouse models overexpressing NF proteins were found to develop motor neuron degeneration and, second, variant alleles of the NF heavy-subunit (NF-H) gene have been found in some human ALS patients. Our axonal transport studies with transgenic mice overexpressing the human NF-H gene, a model of ALS, revealed defects of intracellular transport not only for neurofilament proteins but also for other cytoskeletal proteins and organelles such as mitochondria. Therefore, we propose that neurofilament accumulation in mice causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS.Key words: amyotrophic lateral sclerosis, neurofilaments, transgenic mice, axonal transport.

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Faculty Opinions recommendation of Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1007165.89705 ◽

2002 ◽

Author(s):

Vladimir I Gelfand

Keyword(s):

Axonal Transport ◽

Motor Neurons ◽

Late Onset ◽

Progressive Degeneration

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ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms20205151 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5151 ◽

Cited By ~ 1

Author(s):

Norante ◽

Peggion ◽

Rossi ◽

Martorana ◽

De Mario ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Nervous System Function ◽

Serca Pump ◽

Selective Death ◽

First Time ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.

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Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo

Human Molecular Genetics ◽

10.1093/hmg/ddz190 ◽

2019 ◽

Vol 28 (21) ◽

pp. 3584-3599 ◽

Cited By ~ 4

Author(s):

Matthew G Williamson ◽

Mattéa J Finelli ◽

James N Sleigh ◽

Amy Reddington ◽

David Gordon ◽

...

Keyword(s):

Motor Neurons ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Gene Encoding ◽

Over Expression ◽

Neuromuscular Abnormalities ◽

And Function ◽

Lateral Sclerosis

Abstract A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

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