The biology of TDP-43 stress granules: novel insights about protein aggregation in neurodegenerative diseases
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TDP-43 is the principal protein component in the neuronal inclusion bodies of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD). In afflicted CNS areas, TDP-43 mislocalizes to cytoplasm and forms inclusion bodies. Emerging evidence identifies TDP-43 as an RNA-binding protein that governs RNA metabolism, trafficking and protein translation. Studies in this thesis demonstrate that TDP-43 is a bona fide stress granule (SG)-associated protein, participating in stress granule pathways. Expressing C-terminal fragments of TDP-43, which mimic pathological TDP-43 recovered from diseased-human CNS tissues, are sufficient to elicit SG formation and cytotoxicity, suggesting that pathological TDP-43 interacts with the SG pathway and could impair protein translation and RNA metabolism in neurons. Colocalization of TDP-43 and SG markers in spinal cords of ALS donors supports the hypothesis that pathological TDP-43 associates with SGs to form neuronal inclusions in ALS. We also discovered that ALS-linked mutations in TDP-43 increase its tendency to become insoluble, aggregate, and form SGs. ALS-Iinked mutations in TDP-43 increase its direct interaction with TIA-1, a key molecular organizer and component of SG, suggesting a mechanism by which mutations in TDP-43 could modify the formation and composition of RNA granules generally and SGs specifically. In neurons, proteins are locally translated at dendrites to fulfill the demands of synaptic plasticity in response to neuronal activity changes. Imaging studies performed using primary hippocampal neurons indicate that TDP-43 localizes in both transport RNA granules and SGs at dendrites, but not P-bodies. Importantly the distribution of TDP-43 RNA granules along dendrites is disturbed by ALS-Iinked TDP-43 mutation. Live cell imaging provides us a delicate tool for tracking granule motility. We discovered that disease-linked mutations in TDP-43 dampen the mobility of TDP-43 in RNA granules, and also inhibit the movement of TDP-43-enriched RNA granules. The movement impairment of TDP-43 RNA granules raises the possibility that protein translation and RNA metabolism might be dysregulated locally in dendrites. Overall, our studies on TDP-43 RNA granules provide a new model for protein aggregation in neurodegenerative diseases that is based on the SG pathway, and suggest mechanisms by which mutations in TDP-43 might contribute to disease.
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