# Understanding cellular and molecular mechanisms of neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $330,484

## Abstract

ABSTRACT
The goal to effectively treat neurodegenerative disorders will require an understanding not only of intrinsic
neuronal dysfunction, but also of how non-neuronal cells contribute to neuronal dysfunction. Spinocerebellar
ataxia type 1 (SCA1), is a fatal, dominantly inherited neurodegenerative disease characterized by degeneration
of Purkinje neurons in the cerebellum. Despite intense focus on neuron intrinsic mechanisms, pathogenesis of
SCA1 remains incompletely understood and there are no effective therapies available for SCA1 patients.
Astroglia play fundamental roles in nearly all aspects of neuronal function, and research in other
neurodegenerative diseases demonstrated that they contribute to disease pathogenesis. We have previously
shown that cerebellar astroglia are activated pre-symptomatically in the mouse models of SCA1, and that their
activation correlates with neuronal dysfunction and disease progression.
Our new preliminary data indicate that astroglia have a bi-modal, disease-stage dependent role in the
pathogenesis of SCA1. We have found that astroglia are beneficial pre-symptomatically, whereas they become
harmful after the onset of symptoms. Moreover we have found that these different effects of astroglia are
regulated by NF-κB signaling, one of the key transcriptional regulators of astrogliosis. We have also found that
early in disease NF-κB signaling enhances the expression of neurosupportive genes brain derived
neurotrophic factor (BDNF) and potassium channel Kir4.1 in astroglia, while later in SCA1, NF-κB decreases
expression of these genes.
The objective of this proposal is to test our central hypothesis that early in disease astroglial NF-κB signaling
regulates neuroprotective astroglial phenotype, but switches to regulating harmful astroglial phenotype late in
disease. We propose that mechanistically, NF-κB alters critical supportive functions of astroglia, such as the
ability to promote neuronal survival (BDNF), and maintain homeostasis levels of extracellular ions and
neurotransmitters (Kir4.1) in a stage-of disease specific manner.

## Key facts

- **NIH application ID:** 10145811
- **Project number:** 5R01NS107387-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Marija Cvetanovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,484
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145811

## Citation

> US National Institutes of Health, RePORTER application 10145811, Understanding cellular and molecular mechanisms of neurodegeneration (5R01NS107387-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145811. Licensed CC0.

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