TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy

Gitcho, Michael A.; Bigio, Eileen H.; Mishra, Manjari; Johnson, Nancy; Weıntraub, Sandra; Mesulam, Marsel; Rademakers, Rosa; Chakraverty, Sumi; Cruchaga, Carlos; Morris, John C.; Goate, Alison M.; Cairns, Nigel J.

doi:10.1007/s00401-009-0571-7

Cited by 140 publications

(116 citation statements)

References 63 publications

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“…Overexpression of both mutant and wild-type TDP-43 can cause neurodegeneration in vitro and in vivo (9,15), suggesting that an amplification of wild-type TDP-43 function can be toxic. Recent studies suggest that TDP-43 levels are elevated in familial and sporadic ALS cases (16,17). Furthermore, ALSlinked TDP-43 mutants enhance the stability of TDP-43, consistent with the possibility that TDP-43 mutants mediate their toxicity by increasing the TDP-43 levels (1,18).…”

supporting

confidence: 54%

“…It has been well established that the TDP-43 level is normally maintained constant by an autoregulatory mechanism (46,76), and the observed alterations in alternative splicing may reflect a state of TDP-43 deregulation and dysfunction, which could have a major role in motor neuron degeneration and ALS phenotypes. Indeed it has been reported that TDP-43 levels in human ALS is modestly elevated (16,77). Because TDP-43 functions in multiprotein/RNA complexes, an elevation in the TDP-43 level could disrupt the stoichiometry among the components in the complex, thereby causing dysfunction of the TDP-43 complexes (13).…”

Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vmentioning

confidence: 99%

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Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

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

152

121

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

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supporting

confidence: 54%

Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vmentioning

confidence: 99%

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

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

152

121

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“…Whether mitochondrial abnormality could explain the observed metabolic changes and altered body weight composition of hTDP-43 A315T animals will be subject of future studies. Summary and Outlook-With respect to the fact that patients carrying A315T mutations develop either ALS or motor neuron disease (80,97) and a patient carrying a 3Ј-UTR mutation of TDP-43 leading to overexpression of the protein developed FTLD, the mouse model presented here is interpreted as a predisease model for FTLD-motor neuron disease. In agreement with this interpretation, TARDBP KIA315T animals "Knock-in" TDP-43 Mice and Altered Fatty Acid Metabolism APRIL 11, 2014 • VOLUME 289 • NUMBER 15…”

Section: A315tmentioning

confidence: 99%

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

Stribl

Samara

Trümbach

et al. 2014

Journal of Biological Chemistry

108

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Background: Mutations in TDP-43 are frequently found in ALS patients. Results: A315T TDP-43 protein is elevated from this transgenic knock-in allele due to disturbed feedback regulation. Conclusion: Elevation of A315T TDP-43 was insufficient to cause ALS in this mutant. Significance: This TDP-43 allele could be valuable in determining genetic or environmental factors that cause full-blown FTLD or ALS.

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“…Indeed, pathogenic effects of increased levels of wild-type proteins are common in other neurodegenerative disorders, as exemplified by increased gene dose or overexpression of wild-type TDP-43, α-synuclein, and amyloid β precursor protein (APP) in ALS/FTLD, Parkinson disease, and Alzheimer's disease (16)(17)(18). However, in all these cases (including FUS), it is unclear whether protein overexpression and missense mutations contribute to neurodegenerative disorders via common or distinct mechanisms.…”

mentioning

confidence: 99%

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

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

126

123

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The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS WT ) and a pathological mutation (FUS R521G A myotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 3-5 y of onset. Interestingly, ∼10-15% of ALS patients have clinical features of frontotemporal lobar degeneration (FTLD), marked by a decline in decision-making, behavioral control, emotion, and language, and as many as half have mild-to-moderate cognitive or behavioral abnormalities (1). FTLD comprises a group of heterogeneous diseases characterized by progressive neurodegeneration of the frontal and temporal lobes and clinically by frontotemporal dementia (FTD) with or without motor neuron disease. There is no cure or effective therapy for those who suffer from ALS or FTLD, and the mechanisms by which these diseases occur are not well understood.The clinical, pathological, and genetic overlap between ALS and FTLD suggests that there are mechanisms shared by these diseases. The RNA-binding proteins fused in sarcoma (FUS) and transactive response DNA-binding protein-43 (TDP-43) are the major protein components of inclusions that are characteristic of ALS and FTLD-U (FTLD with ubiquitinated inclusions) (2). More than 50 genetic FUS mutations have been identified in these related neurodegenerative disorders (3). Similarly, more than 40 dominant mutations in the TDP-43 gene have been linked to ALS cases and, to a lesser extent, to FTLD (4). The identification of mutations in the FUS and TDP-43 genes has provided insights for uncovering the disease mechanisms for ALS and FTLD.FUS is a ubiquitously expressed RNA-binding protein that exists in dynamic ribonucleoprotein complexes involved in pre-mRNA splicing, mRNA stability, and mRNA transport. FUS is a member of the FET family of proteins that bind RNAs (5) and contains an RNA recognition motif, three arginine-glycine-glycine (RGG) boxes, and a zinc finger (ZnF) (6). RGG2-ZnF-RGG3 is the major RNA-binding domain, which has a preference for GUrich sequences (7,8). The N terminus of FUS contains a lowcomplexity sequence domain involved in RNA granule formation (9). Nucleocytoplasmic shuttling of FUS occurs by a nonclassical proline-tyrosine nuclear localization signal (PY-NLS) and a nuclear export signal (NES) (10). Methylation of the C-terminal RGG3 domain of FUS is necessary for transportin 1 interaction and nuclear localization (11).The majority of clinical ALS/FTLD-associated FUS mutations occur in its C-terminal PY-NLS seque...

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TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy

Cited by 140 publications

References 63 publications

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

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