Project Details
Description
PROJECT SUMMARY/ABSTRACT: PROJECT 2
Recent studies have documented defects in nuclear transport and stress granule/liquid phase transitions as
potentially early events in C9orf72 repeat expansion model systems. However, little is actually known about
how these initial discoveries relate to ALS vs. FTD, two diseases caused by the same mutation. The
hexanucleotide repeat expansion leads to both aberrant RNA as well as dipeptide repeat (DPR) proteins made
via non-ATG repeat associated translation (RAN translation). A consensus of studies suggests the mutation
disrupts nucleocytoplasmic transport but the mechanism and cell type specificity of this defect remain unclear.
This leads to the important question: how does the same mutation differentially involve cortical neurons versus
spinal motor neurons in clinically distinct diseases? Emerging data also links stress granule-based biology to
nucleocytoplasmic transport in non-neuronal cells. However, whether this is relevant to CNS neurons or glia is
unclear. We will employ a model system based on human induced pluripotent stem cell (iPSC)-derived cortical
neurons and motor neurons from well-defined patients with either C9orf72 FTD, C9orf72 ALS or C9orf72 ALS
and FTD to explore the underlying biological mechanism that may serve to explain the involvement of selective
neuronal and/or glial cell types in these widely differing diseases. Specifically, in Aim 1 we will
comprehensively assess and compare alterations in the nuclear pore complex (NPC) and nucleocytoplasmic
transport in C9orf72 ALS/FTD iPSC-derived motor and cortical neurons. Understanding the differences in
motor and cortical neuron nuclear pore complexes will define fundamental neuron-specific biology and may aid
in dissecting the disease-specific pathogenesis in C9orf72 ALS and FTD. In Aim 2, we propose to elucidate
molecular pathways altered by C9orf72 repeat expansions in iPSC-derived motor and cortical neurons.
Interrogating human cortical versus spinal C9orf72 neurons using “omics” analytics will provide insight into cell-
specific defects and opportunities for mitigating neuronal injury. Finally, in Aim 3, we will investigate the
relationship between cellular stress and alterations in the nuclear pore complex in C9orf72 ALS/FTD.
Determining the contribution of stress granules to dysfunctional nucleocytoplasmic transport will uncover novel
approaches to therapeutic interventions for repairing the nuclear pore complex. In summary, understanding the
connection between disease pathomechanisms and the neuronal subtype-specific effects of the C9orf72
repeat expansion on the nuclear pore complex, nucleocytoplasmic transport, and gene expression are
essential to our understanding of C9orf72 ALS/FTD pathogenesis.
Status | Finished |
---|---|
Effective start/end date | 4/1/20 → 3/31/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $450,313.00
- National Institute of Neurological Disorders and Stroke: $416,838.00
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