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Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons. Causative genes for familial ALS (fALS), e.g. TARDBP or FUS/TLS, have been found, among which mutations within the profilin 1 (PFN1) gene have recently been identified in ALS18. To elucidate the mechanism whereby PFN1 mutations lead to neuronal death, we generated transgenic Drosophila melanogaster overexpressing human PFN1 in the retinal photoreceptor neurons. Overexpression of wild-type or fALS mutant PFN1 caused no degenerative phenotypes in the retina. Double overexpression of fALS mutant PFN1 and human TDP-43 markedly exacerbated the TDP-43-induced retinal degeneration, i.e. vacuolation and thinning of the retina, whereas co-expression of wild-type PFN1 did not aggravate the degenerative phenotype. Notably, co-expression of TDP-43 with fALS mutant PFN1 increased the cytoplasmic localization of TDP-43, the latter remaining in nuclei upon co-expression with wild-type PFN1, whereas co-expression of TDP-43 lacking the nuclear localization signal with the fALS mutant PFN1 did not aggravate the retinal degeneration. Knockdown of endogenous Drosophila PFN1 did not alter the degenerative phenotypes of the retina in flies overexpressing wild-type TDP-43 These data suggest that ALS-linked PFN1 mutations exacerbate TDP-43-induced neurodegeneration in a gain-of-function manner, possibly by shifting the localization of TDP-43 from nuclei to cytoplasm.

SUBMITTER: Matsukawa K

PROVIDER: S-EPMC5095402 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43.

Matsukawa Koji K Hashimoto Tadafumi T Matsumoto Taisei T Ihara Ryoko R Chihara Takahiro T Miura Masayuki M Wakabayashi Tomoko T Iwatsubo Takeshi T

The Journal of biological chemistry 20160915 45

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons. Causative genes for familial ALS (fALS), e.g. TARDBP or FUS/TLS, have been found, among which mutations within the profilin 1 (PFN1) gene have recently been identified in ALS18. To elucidate the mechanism whereby PFN1 mutations lead to neuronal death, we generated transgenic Drosophila melanogaster overexpressing human PFN1 in the retinal photoreceptor neuron ...[more]

PMID: 27634045

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Project description:The G4C2 hexanucleotide repeat expansion mutation in the C9orf72 gene is the most common genetic cause underlying both amyotrophic lateral sclerosis and frontotemporal dementia. Pathologically, these two neurodegenerative disorders are linked by the common presence of abnormal phosphorylated TDP-43 neuronal cytoplasmic inclusions. We compared the number and size of phosphorylated TDP-43 inclusions and their morphology in hippocampi from patients dying with sporadic versus C9orf72-related amyotrophic lateral sclerosis with pathologically defined frontotemporal lobar degeneration with phosphorylated TDP-43 inclusions, the pathological substrate of clinical frontotemporal dementia in patients with amyotrophic lateral sclerosis. In sporadic cases, there were numerous consolidated phosphorylated TDP-43 inclusions that were variable in size, whereas inclusions in C9orf72 amyotrophic lateral sclerosis/frontotemporal lobar degeneration were quantitatively smaller than those in sporadic cases. Also, C9orf72 amyotrophic lateral sclerosis/frontotemporal lobar degeneration homogenized brain contained soluble cytoplasmic TDP-43 that was largely absent in sporadic cases. To better understand these pathological differences, we modelled TDP-43 inclusion formation in fibroblasts derived from sporadic or C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia patients. We found that both sporadic and C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia patient fibroblasts showed impairment in TDP-43 degradation by the proteasome, which may explain increased TDP-43 protein levels found in both sporadic and C9orf72 amyotrophic lateral sclerosis/frontotemporal lobar degeneration frontal cortex and hippocampus. Fibroblasts derived from sporadic patients, but not C9orf72 patients, demonstrated the ability to sequester cytoplasmic TDP-43 into aggresomes via microtubule-dependent mechanisms. TDP-43 aggresomes in vitro and TDP-43 neuronal inclusions in vivo were both tightly localized with autophagy markers and, therefore, were likely to function similarly as sites for autophagic degradation. The inability for C9orf72 fibroblasts to form TDP-43 aggresomes, together with the observations that TDP-43 protein was soluble in the cytoplasm and formed smaller inclusions in the C9orf72 brain compared with sporadic disease, suggests a loss of protein quality control response to sequester and degrade TDP-43 in C9orf72-related diseases.

Project description:Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

Dataset Information

Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43.

Publications

Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43.

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