MCB Joint Seminar Series: Alyssa Coyne

Host: Daniela Zarnescu

"Mechanisms of nucleostasis in neuronal health and disease"

Maintenance of nuclear pore complex (NPC) and nuclear envelope (NE) structure, organization, and function is essential for cellular function. The NPC and NE critically controls multiple cellular processes including nucleocytoplasmic transport (NCT), gene expression, genome organization, and maintains nuclear – cytoplasmic compartmentalization. Alterations to the composition and function of the NPC have recently emerged as an early and significant contributor to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and related neurodegenerative diseases. However, the molecular events leading to this pathological phenomenon remain largely unknown. Using induced pluripotent stem cell (iPSC) derived neurons (iPSNs), postmortem human tissues, and super resolution structured illumination microscopy (SIM), I have comprehensively defined a significant injury to the nuclear pore complex (NPC) as one of the earliest events in ALS pathophysiology. This injury is characterized by the reduction of specific nucleoporins, beginning with POM121, from the neuronal NPC. Mechanistically, I have uncovered that aberrant nuclear accumulation of the ESCRT-III protein CHMP7 initiates NPC injury in ALS to functionally impact nucleocytoplasmic transport, nuclear TDP-43 function and localization, and overall neuronal survival. Critically, reduction of CHMP7 protein mitigates NPC injury and downstream pathogenic events in ALS iPSNs. Collectively, this work has identified a new pathway implicated in neurodegenerative disease pathophysiology that can be therapeutically targeted to alleviate prominent pathogenic cascades. 


October 26, 2021 - 11:00am to 12:15pm
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