Harnessing Reversible Protein Aggregation to Treat Alzheimer's Disease

Benjamin Wolozin, MD, PhD
Boston University (Boston, MA)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2015256S
Award Type:
Standard
Award Region:
US Northeastern
Benjamin Wolozin, MD, PhD

Targeting Stress Granule Biology in Alzheimer’s Disease

Summary

The function of RNA is to help translate the genetic “blueprint” of DNA information into actual proteins that execute the majority of functions in a cell. RNA binding proteins (RBPs) regulate the conversion of messenger RNA to protein through formation of complexes called RNA granules. Chemical stresses induce formation of a particular type of complex termed the stress granules (SG). Our preliminary data showed that the neurofibrillary tangles that accumulate in Alzheimer’s disease (AD) are associated with SGs. We hypothesize that the process of aggregation associated with SGs might actually stimulate pathology in AD. BrightFocus Foundation was the first organization to give us funding for this project. 

Using BrightFocus funds we made the startling finding that tau protein is actually required for SG responses, which means that the pathological changes driving AD are intimately connected to the SG response.  We also showed that SG formation stabilizes tau protein, stimulates tau misfolding, and stimulates formation of the insoluble tau that forms the pathology of AD. Equally important, we showed that removing a SG protein (TIA-1) actually prevents the misfolding of tau associated with AD. This suggests that reducing SG formation might be a novel therapeutic strategy for AD.  

Publications

Silva JM, Rodrigues S, Sampaio-Marques B, Gomes P, Neves-Carvalho A, Dioli C, Soares-Cunha C, Mazuik BF, Takashima A, Ludovico P, Wolozin B, Sousa N, Sotiropoulos I. Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death Differ. 2019 Aug;26(8):1411-1427. doi: 10.1038/s41418-018-0217-1. Epub 2018 Nov 15. PubMed PMID: 30442948 PubMed Icon Google Scholar Icon

Silva JM, Rodrigues S, Sampaio-Marques B, Gomes P, Neves-Carvalho A, Dioli C, Soares-Cunha C, Mazuik BF, Takashima A, Ludovico P, Wolozin B, Sousa N, Sotiropoulos I. Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death Differ. 2018 Nov 15. doi: 10.1038/s41418-018-0217-1. [Epub ahead of print] PubMed PMID: 30442948 PubMed Icon Google Scholar Icon

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