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J Neurosci. 2014 Mar 19;34(12):4167-74. doi: 10.1523/JNEUROSCI.2350-13.2014.

ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor.

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  • 1Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118, and Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.

Abstract

Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction.

KEYWORDS:

G3BP; TIA-1; induced pluripotent stem cells; stress granule; trafficking; translation

PMID:
24647938
[PubMed - indexed for MEDLINE]
PMCID:
PMC3960463
Free PMC Article
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