ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 80 citations in OpenAlex.
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.Cell reports · 2025Article
- TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.bioRxiv : the preprint server for biology · 2024Article
- Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration.Cell reports · 2024Article
- Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Article
- Review
- TDP-43 Oligomerization and Phase Separation Properties Are Necessary for Autoregulation.Frontiers in neuroscience · 2022Article
- Phenotypic diversity in ALS and the role of poly-conformational protein misfolding.Acta neuropathologica · 2021Review
- Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS.The Journal of clinical investigation · 2020Article
- Overexpression of human wtTDP-43 causes impairment in hippocampal plasticity and behavioral deficits in CAMKII-tTa transgenic mouse model.Molecular and cellular neurosciences · 2020Article
- TDP43 and RNA instability in amyotrophic lateral sclerosis.Brain research · 2018Review
- TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia.Scientific reports · 2018Article
- TDP-43 Prions.Cold Spring Harbor perspectives in medicine · 2018Review
- TDP-43 stabilises the processing intermediates of mitochondrial transcripts.Scientific reports · 2017Article
- p62 Pathology Model in the Rat Substantia Nigra with Filamentous Inclusions and Progressive Neurodegeneration.PloS one · 2017Article
- Gene Therapy Models of Alzheimer's Disease and Other Dementias.Methods in molecular biology (Clifton, N.J.) · 2016Article
- Initial gene vector dosing for studying symptomatology of amyotrophic lateral sclerosis in non-human primates.Journal of medical primatology · 2015Article
- Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis.Gene therapy · 2015Article
- TDP-43 suppresses CGG repeat-induced neurotoxicity through interactions with HnRNP A2/B1.Human molecular genetics · 2014Article
- Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease.Frontiers in neuroanatomy · 2014Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Since the discovery of neuropathological lesions made of TDP-43 and ubiquitin proteins in cases of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), there is a burst of effort on finding related familial mutations and developing animal models. We used an adeno-associated virus (AAV) vector for human TDP-43 expression targeted to the substantia nigra (SN) of rats. Though TDP-43 was expressed mainly in neuronal nuclei as expected, it was also expressed in the cytoplasm, and dotted along the plasma membrane of neurons. Cytoplasmic staining was both diffuse and granular, indicative of preinclusion lesions, over 4 weeks. Ubiquitin deposited in the cytoplasm, specifically in the TDP-43 group, and staining for microglia was increased dose-dependently by 1-2 logs in the TDP-43 group, while neurons were selectively obliterated. Neuronal death induced by TDP-43 was pyknotic and apoptotic. TDP-43 gene transfer caused loss of dopaminergic neurons in the SN and their axons in the striatum. Behavioral motor dysfunction resulted after TDP-43 gene transfer that was vector dose-dependent and progressive over time. The cytoplasmic expression, ubiquitination, and neurodegeneration mimicked features of the TDP-43 diseases, and the gliosis, apoptosis, and motor impairment may also be relevant to TDP-43 disease forms involving nigrostriatal degeneration.
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