# Nuclear and Glial Dysfunction in Neurodegeneration

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $1,191,282

## Abstract

Abstract
In the last 5–10-years new model systems, to study ALS, FTD and other dementias, based on patient derived
induced pluripotent cell lines have provide great insight into highly relevant disease-causing pathways as well
as fundamental neuronal and glial cell biology. New studies using these, and other model systems suggest
the nuclear transport is the fundamental injury linked to both familial sporadic ALS and FTD. Emerging
studies now implicate nuclear transport and the nuclear pore complex in multiple different neurodegenerative
diseases including ALS, FTD, Huntington’s disease and even aging. These studies are beginning to identify
candidate therapies for sporadic forms of the disease. The nuclear pore complex is diverse, and mutations of
its constituent proteins can lead to a wide range of different degenerative diseases. Thus, studies of the CNS
nuclear pore and nucleocytoplasmic transport have pathogenic implications that are wide ranging. This
proposal will comprehensively investigate the biology of CNS nuclear pores and nuclear transport- the
fundamental properties in different neuronal and glia, mechanisms by which the nuclear pore is disrupted,
include possibly disease initiating biology involving the ESCT3/CHMP7 pathways, how the nuclear pore
complex is disrupted in sporadic and familial forms of the diseases utilizing several complementary models
including C9-ALS fly and mouse models and iPS neurons and brain tissue from sporadic and C9orf72 mutant
ALS/FTD patients. We will also investigate whether modulation of nucleocytoplasmic transport and /or repair
of the nuclear pore complex may be a therapeutic strategy for ALS/FTD. Our emerging data teach that there
are multiple candidate therapeutic opportunities for this pathway and neurodegeneration. As we have now
learned that defect on the nuclear pore complex are upstream of the disruption of TDP43 nuclear location and
loss of function, this pathway may have relevance to not only ALS and FTD – but other neurological injuries
involving TDP43 misregulation. Finally, studies over the last decade have revealed that neurodegenerative
diseases are not simply a disorder of neurons, but that glial cells also contribute to pathophysiology. Many
studies have implicated aberrant astroglial function in ALS and neurodegeneration. Regional alterations of
astroglia have long been known—but how this occurs and whether astroglia exist as functional/molecular
subtypes has been unclear. New studies from our group and others now suggests real subtypes of astroglia
exist, may have specific functions n modulating cortical dendritic and synaptic biology and may be selectively
altered in ALS. The biology of these newly identified subgroups will be explored in this proposal and how they
alter spines/dendrites, neuronal elements known to be dramatically altered in neurodegeneration.

## Key facts

- **NIH application ID:** 10842316
- **Project number:** 5R35NS132179-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jeffrey D Rothstein
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,191,282
- **Award type:** 5
- **Project period:** 2023-05-16 → 2031-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842316

## Citation

> US National Institutes of Health, RePORTER application 10842316, Nuclear and Glial Dysfunction in Neurodegeneration (5R35NS132179-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10842316. Licensed CC0.

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