Interdisciplinary Initiatives Program Round 12 - 2024
Project Investigators:
Xinnan Wang, Neurosurgery
Judith Frydman, Biology and Genetics
Abstract:
Neurodegenerative diseases are devastating and incurable conditions that are quickly becoming a tremendous economic, societal, and familiar burden, particularly to developed societies where life expectancy has increased. The molecular basis for neurodegeneration remains a critical unanswered question. Research in the field tends to focus on one specific dysfunction as causal for disease, be it accumulation of amyloid aggregates, impairment of specific organelles such as mitochondria or lysosomes, or altered neuronal metabolism. We in contrast hypothesize that neuronal dysfunction arises from the collective impairment of several inter-related processes that are highly interdependent mechanistically and functionally, namely proteostasis, metabolism, mitochondrial integrity, and lysosomal function. In this innovative, and potentially groundbreaking view, neurodegenerative disease would emerge from a vicious cycle of dysfunction that can be triggered genetically or through environmental insults, whereby impairment of one process leads to dysfunction in the others, causing the collapse of neuronal homeostasis. We propose to test this hypothesis by measuring organelle communications in the context of dynamic proteome, metabolome, organelle transport, localization, and structure remodeling across time, space, and perturbation in a neuron, instrumented with the integration of completely distinct expertise and tools of the two PIs.
