Mimicking Aspects of Frontotemporal Lobar Degeneration and Lou Gehrig's Disease in Rats via TDP-43 Overexpression

Tatom, Jason B; Wang, David B.; Dayton, Robert D.; Skalli, Omar; Hutton, Michael; Dickson, Dennis W.; Klein, Ronald L.

doi:10.1038/mt.2009.3

Cited by 75 publications

(70 citation statements)

References 25 publications

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“…TDP-43 proteinopathy is characterized by TDP-43 immunoreactive neuronal and glial inclusion bodies together with a progressive loss of function of the affected neurons. A recent study using an adeno-associated virus vector to express hTDP-43 in substantia nigra (SN) in rats revealed a loss of SN neurons, gliosis, and changes in amphetamine-stimulated rotational behavior (25). Here, we report the generation and characterization of transgenic flies expressing human TDP-43.…”

Section: Discussionmentioning

confidence: 99%

A Drosophila model for TDP-43 proteinopathy

Ray

Rao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

249

227

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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. Recent studies show that TDP-43 is a major protein component of neuronal inclusion bodies in the affected tissues in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) (6, 7), Alzheimer's disease (AD) (8-10), and other types of dementia (10-13). Decreased protein solubility, hyperphosphorylation, abnormal cleavage, and cytoplasmic mislocalization of TDP-43 have been associated with TDP-43 proteinopathy (14-16). It is not clear whether TDP-43 proteinopathy is caused by loss-of-function of TDP-43 or gain-of-function neurotoxicity. Here, we report the generation and characterization of transgenic flies expressing human TDP-43. In different types of neurons, including photoreceptors, mushroom bodies, or motor neurons, simply overexpressing hTDP-43 by itself is sufficient to cause protein aggregate formation and neuronal loss in an agedependent manner, suggesting that increased hTDP-43 expression or aberrant accumulation of hTDP-43 may lead to TDP-43 proteinopathy. Our transgenic flies recapitulate important pathological and clinical features of ALS, representing a powerful animal model for TDP-43 proteinopathy. ResultsGeneration of Transgenic Flies Expressing Human TDP-43. To study human TDP-43 (hTDP-43) in vivo, we used Drosophila, a powerful genetic model widely used to study neurodegeneration (17, 18). We generated transgenic flies expressing monomeric red fluorescent protein (RFP) as a control or hTDP-43 fused to RFP in different populations of neurons using UAS/Gal4 system (19) (Fig. S1C).We also generated transgenic flies expressing a mutant hTDP-43, T202, containing the carboxy...

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Section: Discussionmentioning

confidence: 99%

A Drosophila model for TDP-43 proteinopathy

Ray

Rao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

249

227

View full text Add to dashboard Cite

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“…Thus, several studies report an increase of TDP-43 mRNA levels in the brains of patients affected by various forms of frontotemporal lobar degeneration (FTLD) (Mishra et al 2007;Chen-Plotkin et al 2008;Kabashi et al 2008;Weihl et al 2008). Moreover, we know from several recent animal models and adeno-associated virus (AAV) overexpression systems that raising TDP-43 concentrations can lead to neurodegeneration (Tatom et al 2009;Barmada et al 2010;Li et al 2010;Liachko et al 2010;Wils et al 2010;Xu et al 2010;Wegorzewska and Baloh 2011). We predict that a deeper understanding of the mechanisms that control production of TDP-43 within the cell may lead to the development of improved therapeutic approaches for these pathologies.…”

Section: Tdp-43 Overexpression Blocks Recognition Of Pa 1 By Cstf-64mentioning

confidence: 99%

Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection

Avendaño‐Vázquez¹,

Dhir²,

Bembich³

et al. 2012

Genes Dev.

164

178

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TDP-43 is a critical RNA-binding factor associated with pre-mRNA splicing in mammals. Its expression is tightly autoregulated, with loss of this regulation implicated in human neuropathology. We demonstrate that TDP-43 overexpression in humans and mice activates a 39 untranslated region (UTR) intron, resulting in excision of the proximal polyA site (PAS) pA 1 . This activates a cryptic PAS that prevents TDP-43 expression through a nuclear retention mechanism. Superimposed on this process, overexpression of TDP-43 blocks recognition of pA 1 by competing with CstF-64 for PAS binding. Overall, we uncover complex interplay between transcription, splicing, and 39 end processing to effect autoregulation of TDP-43.

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“…On the other hand, overexpression of the fulllength or N-terminus-truncated TDP-43 in yeast is toxic and forms cytoplasmic aggregates 22 . The rats injected with a viral TDP-43 construct have undergone neuronal apoptosis 23 , and TDP-43 transgenic mice partially recapitulate ALS and FTLD-TDP 24,25 . Despite the emerging biological studies on the pathogenic role of TDP-43, several studies have suggested that RRM1 (refs 26,27), RRM2 (ref.…”

mentioning

confidence: 99%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

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Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-b to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.

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Mimicking Aspects of Frontotemporal Lobar Degeneration and Lou Gehrig's Disease in Rats via TDP-43 Overexpression

Cited by 75 publications

References 25 publications

A Drosophila model for TDP-43 proteinopathy

A Drosophila model for TDP-43 proteinopathy

Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

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