# Investigating the Role of GDE2 in Neuronal Mitotic Inhibition and Nuclear Pore Complex Defects

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2021 · $46,036

## Abstract

Project Summary / Abstract
Alzheimer's disease (AD) and related diseases (ADRDs) are the leading cause of dementia, affecting millions of
people each year. Despite being such a prevalent public health concern, knowledge of the etiology of
neurodegeneration in these diseases is limited and has stymied the development of effective treatments.
Aberrant neuronal cell-cycle reentry (CCR) and nuclear pore complex (NPC)/nucleocytoplasmic transport
defects have been separately identified as causal phenomena for neurodegeneration in AD and ADRDs.
However, the mechanisms leading to these phenomena and the relationship between them remains unknown.
We have identified a pathway involving Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) that
prevents CCR and NPC/nucleocytoplasmic transport defects in the adult mammalian brain and is disrupted in
human postmortem AD and ALS brain tissue. GDE2 is one of three six-transmembrane enzymes that act at the
cell surface to cleave the GPI-anchor that tethers some proteins to the membrane. During embryogenesis, GDE2
inhibits progenitor cell proliferation to promote neuronal differentiation. Preliminary studies show that loss of
GDE2 in the adult brain leads to CCR and NPC abnormalities that precede overt neurodegeneration. Because
NPC defects are coincident with CCR in neurons lacking GDE2, and the NPC normally breaks down during
mitosis, we hypothesize that GDE2 is important for maintaining neurons in a postmitotic state throughout life and
that aberrant CCR elicited by GDE2 loss leads to NPC breakdown and neurodegeneration. Importantly, GDE2
localization and function is disrupted in AD and ADRDs, raising the possibility that dysfunction of the GDE2
pathway could contribute to the pathogenesis of these diseases. This proposal will test our central hypothesis in
three aims. Aim 1 will define the physiological requirement for GDE2 in maintaining neuronal quiescence and
NPC integrity in aging mice while Aim 2 will define the relationship between CCR and NPC breakdown and
identify the mechanisms leading to CCR and NPC defects. Later experiments will determine relevance of this
pathway to CCR and NPC disruption in human AD and ADRDs (Aim 3). The proposed research is expected to
identify a novel physiological pathway that is essential for neuronal survival and will provide new insight into
causal mechanisms of neurodegeneration that are relevant to human disease. In addition, this project has
immense training potential. I will have the opportunity to improve my knowledge in neuroscience and cell biology,
and to acquire technical expertise in primary cell culture, viral construct design and transduction, mouse genetics,
brain dissections and tissue preparation, and immunohistochemical analysis of human tissues. This research
will be performed in a highly collaborative environment, where I will have numerous opportunities to receive
quality mentorship and training, to develop my written and presentation skills, and to...

## Key facts

- **NIH application ID:** 10231661
- **Project number:** 1F31AG072745-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Anna Nicole Westerhaus
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-04-13 → 2024-04-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231661

## Citation

> US National Institutes of Health, RePORTER application 10231661, Investigating the Role of GDE2 in Neuronal Mitotic Inhibition and Nuclear Pore Complex Defects (1F31AG072745-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10231661. Licensed CC0.

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