2021 |
Coyne, Alyssa |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. |
Mechanisms of Nuclear Pore Complex Homeostasis and Injury in Als/Ftd and Related Neurodegenerative Diseases @ Johns Hopkins University
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) comprise a spectrum of devastating and fatal neurodegenerative diseases. While over 20 genetic loci have been linked to ALS and FTD, about 90% of ALS cases are sporadic in nature. Recent studies have identified alterations in the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) as a prominent pathomechanism underlying familial and sporadic ALS. However, the molecular mechanisms underlying these pathologic disruptions remain largely unknown. Our recent studies have established that there is a reproducible and robust reduction of eight nucleoporins (Nups) from the NPC in C9orf72 iPSN and postmortem patient neuronal nuclei. Recent work suggests that the ESCRT-III pathway plays a fundamental role in the surveillance and maintenance of properly assembled and functioning NPCs in yeast. Critically, work in these non-CNS systems suggests that recruitment of CHMP7 to the nuclear envelope initiates downstream events leading to degradation of Nups and NPCs. Indeed, the reduction of Nups from the NPC in C9orf72 human neurons appears to be the result of aberrant activation of CHMP7 and ESCRT-III mediated degradation pathways and not the result of Nup mislocalization or alterations in Nup mRNA metabolism. However, little is actually known about how these initial discoveries relate to the far more common sporadic ALS (sALS). Using super resolution structured illumination microscopy (SIM) on a subset of sALS iPSC derived spinal neurons, we have generated preliminary data that strongly suggests NPC and Nup defects are a prevalent pathology in sALS. Notably, in about 50% of sALS iPSNs and postmortem motor cortex samples examined to date, we also observe robust CHMP7 pathology, reminiscent of our studies in C9orf72 ALS/FTD. Collectively, these early studies have led us to hypothesize that in human neurons, aberrant activation of the ESCRT-III pathway may be a substantial contributor to disruptions in the NPC, NCT, and overall cellular survival thus highlighting the potential for CHMP7 as a therapeutic target in ALS and related neurodegenerative diseases characterized by NPC injury. Here, we will use iPSNs and postmortem human CNS tissue to comprehensively define the alterations to individual Nups and NPCs in sALS pathogenesis (Aim 1). Furthermore, we will evaluate the contribution of CHMP7 and aberrant ESCRT-III mediated degradation to NPC injury in sALS (Aim 2). Finally, we will define the mechanism by which CHMP7 is pathologically ?activated? to initiate NPC injury in sALS (Aim 3). Collectively, these experiments will significantly advance our understanding of the mechanisms underlying NPC homeostasis in human neurons and sALS disease and provide novel insights into potential new therapeutic targets. Moreover, the proposed studies will set the stage for future investigations into the role of CHMP7 and Nup degradation in the pathogenesis of FTD and other related neurodegenerative diseases.
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