Please use this identifier to cite or link to this item: https://doi.org/10.1186/s40478-015-0212-4
Title: Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS
Authors: Mitchell, J.C
Constable, R
So, E
Vance, C
Scotter, E
Glover, L
Hortobagyi, T
Arnold, E.S
Ling, S.-C 
McAlonis, M
Da Cruz, S
Polymenidou, M
Tessarolo, L
Cleveland, D.W
Shaw, C.E
Keywords: DNA binding protein
leukocyte antigen
nerve protein
TDP-43 protein, human
age
amyotrophic lateral sclerosis
animal
brain cortex
C57BL mouse
cytoplasm
disease course
disease model
gene expression regulation
genetics
human
metabolism
mouse
mutation
nerve cell
pathology
pathophysiology
spinal cord
transgenic mouse
Age Factors
Amyotrophic Lateral Sclerosis
Animals
Antigens, CD
Cerebral Cortex
Cytoplasm
Disease Models, Animal
Disease Progression
DNA-Binding Proteins
Gene Expression Regulation
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Nerve Tissue Proteins
Neurons
Spinal Cord
Issue Date: 2015
Citation: Mitchell, J.C, Constable, R, So, E, Vance, C, Scotter, E, Glover, L, Hortobagyi, T, Arnold, E.S, Ling, S.-C, McAlonis, M, Da Cruz, S, Polymenidou, M, Tessarolo, L, Cleveland, D.W, Shaw, C.E (2015). Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS. Acta neuropathologica communications 3 : 36. ScholarBank@NUS Repository. https://doi.org/10.1186/s40478-015-0212-4
Rights: Attribution 4.0 International
Abstract: RESULTS: Expression of human wild-type TDP-43 (TDP-43(WT)) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43(Q331K)) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43(WTxQ331K)) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8-10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex, with TDP-43, ubiquitin and p62 cytoplasmic inclusions and an increase in insoluble TDP-43. Nuclear clearance of TDP-43 was not observed in TDP-43(Q331K) mice but was seen in 65 % of aggregate containing spinal cord motor neurons in TDP-43(WTxQ331K) mice.CONCLUSIONS: We hypothesise that cytoplasmic TDP-43(Q331K) aggregates facilitate the recruitment of WT protein in compound animals, which dramatically accelerates neurodegeneration and disease progression. The exploration of disease mechanisms in slow and rapid disease models of TDP-43 proteinopathy will help elucidate novel drug targets and provide a more informative platform for preclinical trials.INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS.
Source Title: Acta neuropathologica communications
URI: https://scholarbank.nus.edu.sg/handle/10635/180330
ISSN: 20515960
DOI: 10.1186/s40478-015-0212-4
Rights: Attribution 4.0 International
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