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Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
- Source :
- Acta neuropathologica, vol 133, iss 6, Acta Neuropathologica
- Publisher :
- Springer Nature
-
Abstract
- Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1698-6) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Male
Pathology
Aging
Motor neuron
TDP-43
Mutant
Frontotemporal dementia (FTD)
Neurodegenerative
Microgliosis
Inbred C57BL
Transgenic
Mice
0302 clinical medicine
80 and over
2.1 Biological and endogenous factors
Amyotrophic lateral sclerosis (ALS)
Aetiology
Amyotrophic lateral sclerosis
Aged, 80 and over
Motor Neurons
Neurodegeneration
Middle Aged
3. Good health
Astrogliosis
DNA-Binding Proteins
medicine.anatomical_structure
Non-cell autonomous
Neurological
Disease Progression
Female
Frontotemporal dementia
Adult
medicine.medical_specialty
Central nervous system
Clinical Sciences
Neuromuscular Junction
Clinical Neurology
Mice, Transgenic
and over
Biology
Motor Activity
Neuromuscular junction
Mouse model
Pathology and Forensic Medicine
03 medical and health sciences
Young Adult
Cellular and Molecular Neuroscience
Rare Diseases
mental disorders
Genetics
medicine
RanGAP1
Animals
Humans
Aged
Inflammation
Original Paper
Neurology & Neurosurgery
Animal
Amyotrophic Lateral Sclerosis
Neurosciences
nutritional and metabolic diseases
medicine.disease
Brain Disorders
nervous system diseases
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Disease Models
Mutation
Neurology (clinical)
ALS
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 00016322
- Volume :
- 133
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica
- Accession number :
- edsair.doi.dedup.....f95edfe70808cf471f8c7eedbb656c91
- Full Text :
- https://doi.org/10.1007/s00401-017-1698-6