Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing public health challenges, for which effective treatment is still lacking. At least two major themes have emerged from the studies of ALS/FTD, concerning etiology related to both RNA metabolism and protein homeostasis. However, the RNA- and protein-based pathogenesis are likely to be interdependent. Here we propose to unravel the key molecular pathways in the common pathogenic processes at the intersection of RNA and protein homeostasis. FUS is one of the RNA-binding proteins that have linked to ALS/FTD. Recently, we discovered a new role for RNA-binding proteins, as exemplified by FUS, in the direct regulation of the activities of microRNAs, which are small RNAs functioning as critical regulators of gene expression. Moreover, considering the notion that FUS protein is capable of undergoing phase separation, assembling into stress granules, and forming protein aggregates, and building on our preliminary evidence, we propose to elucidate the previously unrecognized mechanisms through which aberrant formation of stress granules and protein aggregates disrupt the RNA homeostasis maintained by ALS/FTD associated proteins. Furthermore, our studies will be directed at uncovering the cellular quality control systems that are built in to maintain the RNA/protein homeostasis and understanding how these systems go awry in diseases. Our unique potential to contribute to this field is both conceptual and technical: We have developed a unique combination of biochemical/C. elegans/mammalian systems to study the mechanisms of neurodegeneration, and our recent success bodes well for future plans. The findings will not only provide novel understandings of the molecular causes of disease for key ALS genes but also suggest new strategies for harnessing the cellular defense system to prevent and treat the relevant forms of ALS and other related neurodegenerative diseases. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address these devastating diseases.

Public Health Relevance

Neurodegenerative diseases are becoming an increasingly relevant public health challenge in our aging society. The mechanisms underlying most of these neurodegenerative conditions such as amyotrophic lateral sclerosis and frontotemporal dementia remain poorly understood. The work in this proposal will elucidate the basic pathogenic mechanisms and the novel regulatory pathways particularly at the intersection of RNA and protein homeostasis, providing much needed insights into understanding specific forms of the neurodegenerative diseases as well as new strategies for developing therapeutic interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gubitz, Amelie
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Johns Hopkins University
Schools of Public Health
United States
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