期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 3, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s40478-015-0212-4
关键词
TDP-43; Amyotrophic lateral sclerosis; Mouse
资金
- Medical Research Council
- Wellcome Trust [089701/Z/09/2]
- Motor Neuron Disease Association
- Heaton Ellis Trust
- Psychiatry Research Trust
- American Amyotrophic Lateral Sclerosis Association
- ARRA grant from the National Institutes of Health
- Muscular Dystrophy Association
- Ludwig Institute
- MRC [G0900635, G1100695, G0500289, MC_G1000733, G0900688] Funding Source: UKRI
- Medical Research Council [G0500289, G1100695, MC_G1000733, G0900688, G0900635] Funding Source: researchfish
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 similar to 90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS. 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.
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