Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43
| Autor: | Adam K. Walker, Virginia M.-Y. Lee, Linda K. Kwong, Guanghui Ge, Kalyan Tripathy, John Q. Trojanowski, Melissa Zhou, Krista Spiller, Allen Zheng, Yan Xu |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Cytoplasm Pathology medicine.medical_specialty Biology Article Pathology and Forensic Medicine Random Allocation Cellular and Molecular Neuroscience Atrophy mental disorders medicine Animals Humans Amyotrophic lateral sclerosis Muscle Skeletal Cell Nucleus Mice Inbred C3H Muscle Denervation Movement Disorders Amyotrophic Lateral Sclerosis Neurodegeneration Brain nutritional and metabolic diseases Recovery of Function Frontotemporal lobar degeneration Motor neuron Spinal cord medicine.disease nervous system diseases Cell biology DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Spinal Cord Doxycycline Female Neurology (clinical) Neuron Frontotemporal Lobar Degeneration |
| Zdroj: | Acta Neuropathologica. 130:643-660 |
| ISSN: | 1432-0533 0001-6322 |
| DOI: | 10.1007/s00401-015-1460-x |
| Popis: | Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (ΔNLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43ΔNLS in these ‘regu-latable NLS’ (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43ΔNLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery. |
| Databáze: | OpenAIRE |
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