ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor.
J Neurosci
; 34(12): 4167-74, 2014 Mar 19.
Article
en En
| MEDLINE
| ID: mdl-24647938
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
ARN
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Gránulos Citoplasmáticos
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Dendritas
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Proteínas de Unión al ADN
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Esclerosis Amiotrófica Lateral
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Neuronas
Límite:
Animals
Idioma:
En
Año:
2014
Tipo del documento:
Article