ALS-Linked Mutations Enlarge TDP-43-Enriched Neuronal RNA Granules in the Dendritic Arbor

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Bibliographische Detailangaben
Zeitschriftentitel:	The Journal of Neuroscience
Personen und Körperschaften:	Liu-Yesucevitz, LiQun, Lin, Amy Y., Ebata, Atsushi, Boon, Joon Y., Reid, Whitney, Xu, Ya-Fei, Kobrin, Kendra, Murphy, George J., Petrucelli, Leonard, Wolozin, Benjamin
In:	The Journal of Neuroscience, 34, 2014, 12, S. 4167-4174
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	Society for Neuroscience
Schlagwörter:	General Neuroscience

Details
Zusammenfassung:	<jats:p>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.</jats:p>
Umfang:	4167-4174
ISSN:	0270-6474 1529-2401
DOI:	10.1523/jneurosci.2350-13.2014