INVESTIGATOR: Claudia Fallini, University of Rhode Island
MENTOR: William Van Nostrand, University of Rhode Island

SCIENTIFIC THEME: Neuroscience

ABSTRACT: A detailed insight into the molecular defects leading to neuronal death in ALS/FTD is still missing, hindering the development of a cure. Defects in the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) have been proposed to play a central role in ALS/FTD pathology. However, it remains a gap in our knowledge what are the mechanisms, consequences, and pathogenic relevance of impaired NCT on neuronal resilience in neurodegenerative diseases and during aging. The objective of this application is to identify at the mechanistic level the specific cellular and molecular pathways that are dysfunctional and cause the failure of the NCT ultimately leading to neurodegeneration. In particular, we will test the hypothesis that the actin cytoskeleton is a main modulator of nuclear stability and NPC function, and that changes to this pathway caused by ALS/FTD mutant proteins lead to a diminished ability of neurons to cope with stress and physiological stimulation.

HUMAN HEALTH RELEVANCE: Neurodegenerative diseases such as ALS/FTD represent an outsized burden to a progressively aging population, and no cure exists to alleviate symptoms or stop the progression of these diseases. The proposed research is expected to elucidate at the mechanistic level the molecular pathways underlying cellular pathology in human ALS/FTD neurons. We anticipate that this research will identify novel targets for the development of innovative therapeutic strategies for ALS/FTD and potentially other diseases.