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

Hanson, Keith A.; Kim, Sang Hwa; Wassarman, David A.; Tibbetts, Randal S.

doi:10.1074/jbc.c109.078527

Cited by 118 publications

(122 citation statements)

References 28 publications

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“…The elevation of glutamate concentration causes neurotoxicity through overactivation of ionotropic glutamate receptors (Arundine and Tymianski, 2004;Hanson et al, 2010;Hardingham et al, 2002;Lee et al, 1999;Rothstein et al, 1990;Sarraf-Yazdi et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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SummaryThe dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP-43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance.

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Section: Introductionmentioning

confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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“…These findings support the notion that loss of normal TDP-43 function may contribute to the pathogenesis of ALS and FTLD. On the other hand, ubiquitous or tissue-specific overexpression of either dTDP or human TDP-43 also recapitulated key hallmark features of ALS pathology including premature lethality, neuronal loss, neuromuscular junctions architecture defects and locomotor deficits (Elden, et al, 2010;Estes, et al, 2011;Hanson, et al, 2010;Li, et al, 2010;Lu, et al, 2009;Miguel, et al, 2011;Ritson, et al, 2010;Voigt, et al, 2010). Furthermore, TDP-43 expression appears to be independent of ALS/FTLD-linked mutations (Elden, et al, 2010;Estes, et al, 2011;Ritson, et al, 2010;Voigt, et al, 2010).…”

Section: Drosophila Tdp-43 Modelsmentioning

confidence: 94%

“…Interestingly, upregulation of Pab1-binding protein 1 (Pbp1), an ortholog of the human ATXN2 gene, in a transgenic model of TDP-43 enhanced TDP-43 toxicity and led to a more severe TDP-43 associated phenotypes (Elden, et al, 2010). Similarly, overexpression of ubiquilin 1, a previously identified TDP-43 interacting partner , reduced steady-state TDP-43 expression but enhanced the severity of TDP-43 phenotypes (Hanson, et al, 2010). Another study also showed that the TDP-43 associated phenotypes observed in a transgenic Drosophila TDP-43 model was modulated by coexpression of valosin-containing protein (VCP), a member of the ATPases associated with multiple cellular activities (AAA+) family of proteins regulating a wide array of cellular processes (Ritson, et al, 2010).…”

Section: Drosophila Tdp-43 Modelsmentioning

confidence: 99%

“…These results also support the view of a toxic dominant gain-offunction mechanism(s) associated with TDP-43 proteinopathies. To further explore the role of TDP-43 pathogenesis and identify pathogenic mechanisms, several independent research groups have used different genetic approaches to identify modifier genes that could suppress or enhance TDP-43 toxicity (Elden, et al, 2010;Hanson, et al, 2010;Ritson, et al, 2010). Interestingly, upregulation of Pab1-binding protein 1 (Pbp1), an ortholog of the human ATXN2 gene, in a transgenic model of TDP-43 enhanced TDP-43 toxicity and led to a more severe TDP-43 associated phenotypes (Elden, et al, 2010).…”

Section: Drosophila Tdp-43 Modelsmentioning

confidence: 99%

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In Vivo and In Vitro Models to Study Amyotrophic Lateral Sclerosis

Berthod¹,

Gros‐Louis²

2012

Amyotrophic Lateral Sclerosis

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“…In summary, expression of human TDP-43 in the fly causes gross pathologies similar to those observed in ALS patients: neuronal degeneration, motor neuron deficits, and shortened lifespan ( Figure 6) (Elden et al 2010;Hanson et al 2010;Li et al 2010;Ritson et al 2010;Voigt et al 2010;Estes et al 2011;Kim et al 2014). At a more detailed level, the TDP-43-expressing flies also mimic molecular pathologies such as mislocalization of the protein to the cytoplasm and disease-associated phosphorylation (Hanson et al 2010;Li et al 2010;Estes et al 2011;Choksi et al 2014). Mutant forms of TDP-43, that lack the ability to bind RNA confer little toxicity in the fly compared to the normal protein (Voigt et al 2010), indicating that it is not aggregation, but the disruption to RNA pathways that is important to TDP-43 toxicity.…”

Section: Modeling Rna-based Mechanisms Of Toxicity Of Als/ftd In the Flymentioning

confidence: 99%

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

2015

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With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research.

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

Cited by 118 publications

References 28 publications

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

In Vivo and In Vitro Models to Study Amyotrophic Lateral Sclerosis

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

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