A Drosophila model for TDP-43 proteinopathy
Yan Li,Payal Ray,Elizabeth J. Rao,Chen Shi,Chen Shi,Weirui Guo,Xiaoping Chen,Elvin A. Woodruff,Kazuo Fushimi,Jane Y. Wu +9 more
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TLDR
Transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP- 43 proteinopathy, providing a powerful animal model for this group of devastating diseases.Abstract:
Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy.read more
Citations
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TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration
TL;DR: Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and FTLD have initiated a shifting paradigm for the underlying pathogenesis of multiple neurodegenerative diseases.
Journal ArticleDOI
TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
TL;DR: TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies because of the striking functional and structural similarities of these proteins, which imply that abnormal RNA metabolism is a pivotal event in neurodegeneration.
Journal ArticleDOI
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
TL;DR: Experimental studies are attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein, and the distinct possibility of pleotropic or combined effects.
Journal ArticleDOI
The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease
TL;DR: Simple prion-like transfer mechanisms involving the prion domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system.
Journal ArticleDOI
Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue
Liqun Liu-Yesucevitz,Aylin Bilgutay,Yong Jie Zhang,Tara Vanderwyde,Allison Citro,Tapan Mehta,Nava Zaarur,Ann C. McKee,Robert Bowser,Michael Y. Sherman,Leonard Petrucelli,Benjamin Wolozin +11 more
TL;DR: It is shown that TDP-43 can be induced to form inclusions in cell culture and that most T DP-43 inclusions co-localize with SGs, which are cytoplasmic RNA granules that consist of mixed protein - RNA complexes.
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A Drosophila model of Parkinson's disease
Mel B. Feany,Welcome Bender +1 more
TL;DR: The Drosophila model recapitulates the essential features of the human disorder, and makes possible a powerful genetic approach to Parkinson's disease.
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