Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching

Lu, Yubing; Ferris, Jacob; Gao, Fen‐Biao

doi:10.1186/1756-6606-2-30

Cited by 116 publications

(129 citation statements)

References 38 publications

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“…Experiments performed in vitro demonstrate that CTFs readily aggregate and form fibrillar structures (19,20). However, CTF expression in transgenic flies is well tolerated without neurotoxicity or motor phenotypes (21,22). This raises the question of whether TDP-43 CTFs initiate the formation of TDP-43 inclusions and play a role in neurotoxicity.…”

mentioning

confidence: 97%

A “Two-hit” Hypothesis for Inclusion Formation by Carboxyl-terminal Fragments of TDP-43 Protein Linked to RNA Depletion and Impaired Microtubule-dependent Transport

Pesiridis¹,

Tripathy²,

Tanik³

et al. 2011

Journal of Biological Chemistry

100

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Carboxyl-terminal fragments (CTFs) of TDP-43 aggregate to form the diagnostic signature inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but the biological significance of these CTFs and how they are generated remain enigmatic. To address these issues, we engineered mammalian cells with an inducible tobacco etch virus (TEV) protease that cleaves TDP-43 containing a TEV cleavage site. Regions of TDP-43 flanking the second RNA recognition motif (RRM2) are efficiently cleaved by TEV, whereas sites within this domain are more resistant to cleavage. CTFs containing RRM2 generated from de novo cleavage of nuclear TDP-43 are transported to the cytoplasm and efficiently cleared, indicating that cleavage alone is not sufficient to initiate CTF aggregation. However, CTFs rapidly aggregated into stable cytoplasmic inclusions following de novo cleavage when dynein-mediated microtubule transport was disrupted, RNA was depleted, or natively misfolded CTFs were introduced into these cells. Our data support a "two-hit" mechanism of CTF aggregation dependent on TDP-43 cleavage.The heterogeneous nuclear ribonucleoprotein (hnRNP) 2 TDP-43 (TAR DNA-binding protein of 43 kDa) forms pathological inclusions that are diagnostic hallmarks of amyotrophic lateral sclerosis (ALS) and the major form of frontotemporal lobar degeneration (FTLD-TDP) (1). Missense mutations in TDP-43 provide a genetic link between hnRNP functions and motor neuron disease (2, 3). TDP-43 is predominantly localized to the nucleus, where it regulates RNA splicing, mRNA stability, microRNA processing, and transcription (4 -6). However, in neurodegenerative TDP-43 proteinopathies like ALS and FTLD-TDP, a loss of nuclear TDP-43 coincides with cytoplasmic TDP-43 inclusions (1). These inclusions contain full-length TDP-43 and TDP-43 C-terminal fragments (CTFs) that are hyperphosphorylated and ubiquitinated. However, it is unclear how each of these species of TDP-43 contributes to inclusion formation or disease pathogenesis.TDP-43 is a typical 2XRRM-gly hnRNP composed of two tandem RNA recognition motifs (RRM1 and RRM2) followed by a glycine-rich carboxyl terminus ( Fig. 1) (7). Both RRMs retain nucleic acid binding properties, yet only RRM1 appears essential for RNA splicing (8). The glycine-rich domain is proposed to interact with other hnRNPs to synergistically affect alternative splicing of specific RNA transcripts (9, 10). A common feature of shuttling hnRNPs involved in RNA splicing is that their nuclear export is coupled to the export and maturation of mRNA in distinct ribonucleoprotein (RNP) complexes (11,12). In this respect, the nucleocytoplasmic shuttling of TDP-43 is dependent on its bipartite importin-␣ nuclear localization signal, a chromosome maintenance region 1 (CRM-1) nuclear export signal in RRM2, and undefined aspects of the carboxyl-terminal glycine-rich domain (13,14).CTFs are signatures of disease exclusively associated with TDP-43 pathology, and CTFs cleaved in the middle of RRM2 extending from amino acid 208 to t...

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mentioning

confidence: 97%

A “Two-hit” Hypothesis for Inclusion Formation by Carboxyl-terminal Fragments of TDP-43 Protein Linked to RNA Depletion and Impaired Microtubule-dependent Transport

Pesiridis¹,

Tripathy²,

Tanik³

et al. 2011

Journal of Biological Chemistry

100

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“…Alterations in nuclear processes may arise due to the total dose of human and fly TDP-43 exceeding a certain threshold, above which the protein has a toxic gain-of-function. Alternatively, wild-type human TDP-43 may dominantly interfere with the endogenous Drosophila homolog, the functional knockdown of which has been found to alter expression of specific mRNAs (29) and result in reduced dendritic branching (30). Importantly, we do see a small amount of TDP-43 in the cytosol, but the absence of aggregation suggests either that protein levels are not sufficiently high or that cytosolic TDP-43 is efficiently handled by the UPR and does not accumulate sufficiently to form insoluble aggregates.…”

Section: Ubqln Reduces Tdp-43 Protein Levels and Does Notmentioning

confidence: 99%

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

Hanson¹,

Kim

Wassarman

et al. 2010

Journal of Biological Chemistry

118

107

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“…Loss-of-function models in invertebrates and zebrafish have shown a wide range of defects, ranging from embryonic lethality to morphological and functional defects of the nervous system, vascular system, and muscle degeneration (27,31,(34)(35)(36)(37). In mammalian species, TDP-43 gene deletion leads to early embryonic lethality (38)(39)(40)(41).…”

Section: Significancementioning

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

125

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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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Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching

Cited by 116 publications

References 38 publications

A “Two-hit” Hypothesis for Inclusion Formation by Carboxyl-terminal Fragments of TDP-43 Protein Linked to RNA Depletion and Impaired Microtubule-dependent Transport

A “Two-hit” Hypothesis for Inclusion Formation by Carboxyl-terminal Fragments of TDP-43 Protein Linked to RNA Depletion and Impaired Microtubule-dependent Transport

Ubiquilin Modifies TDP-43 Toxicity in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

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

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