Abstract
Pathological changes involving TDP-43 protein ('TDP-43 proteinopathy') are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.
Keywords:
ALS; Alzheimer’s disease; FTLD; FUS; NEAT1; TDP-43; drosophila; frontotemporal dementia; neurodegeneration; proteinopathy; yeast.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / etiology
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Amyotrophic Lateral Sclerosis / metabolism
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Amyotrophic Lateral Sclerosis / pathology
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Amyotrophic Lateral Sclerosis / prevention & control*
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Animals
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Brain / metabolism*
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Brain / pathology
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DNA-Binding Proteins / toxicity*
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Disease Models, Animal
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Drosophila melanogaster
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Frontotemporal Dementia / etiology
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Frontotemporal Dementia / metabolism
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Frontotemporal Dementia / pathology
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Frontotemporal Dementia / prevention & control*
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neuroblastoma / etiology
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Neuroblastoma / prevention & control*
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RNA, Long Noncoding / administration & dosage
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RNA, Long Noncoding / genetics*
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Saccharomyces cerevisiae
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TDP-43 Proteinopathies / etiology
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TDP-43 Proteinopathies / metabolism
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TDP-43 Proteinopathies / pathology
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TDP-43 Proteinopathies / prevention & control*
Substances
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DNA-Binding Proteins
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NEAT1 long non-coding RNA, human
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RNA, Long Noncoding
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TARDBP protein, human