期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 45, 期 3, 页码 486-499出版社
HUMANA PRESS INC
DOI: 10.1007/s12031-011-9610-7
关键词
TDP-43; Neurodegeneration; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; Transgenic animal models
资金
- Mayo Clinic Foundation
- National Institutes of Health/National Institute on Aging [R01AG026251]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01, R21 NS074121-01]
- Amyotrophic Lateral Sclerosis Association
- Department of Defense [W81XWH-10-1-0512-1, W81XWH-09-1-0315]
Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions, much effort has been directed towards ascertaining how TDP-43 contributes to the pathogenesis of disease. As with other protein misfolding disorders, TDP-43-mediated neuronal death is likely caused by both a toxic gain and loss of TDP-43 function. Indeed, the presence of cytoplasmic TDP-43 inclusions is associated with loss of nuclear TDP-43. Moreover, post-translational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage into C-terminal fragments, may bestow toxic properties upon TDP-43 and cause TDP-43 dysfunction. However, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neurotoxicity. Additionally, given our incomplete understanding of the roles of TDP-43, both in the nucleus and the cytoplasm, it is difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. The development of TDP-43 transgenic animal models is expected to narrow these gaps in our knowledge. The aim of this review is to highlight the key findings emerging from TDP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration.
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