# Neuronal cell-cycle re-entry and neurodegeneration

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $656,416

## Abstract

Two causal mechanisms of neurodegeneration that are found in Alzheimer's disease (AD) and AD-related
diseases such as amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) are re-initiation of the mitotic
cell-cycle in neurons, and impaired nucleocytoplasmic trafficking resulting from disruptions in the nuclear
envelope (NE) and nuclear pore complex (NPC). Deeper insight into how these abnormalities arise would clarify
approaches to design effective treatments for these diseases; however, very little is known about the initiating
mechanisms involved. This application will test the hypothesis that neuronal quiescence is maintained
throughout life via active mechanisms that inhibit the mitotic cell-cycle and that re-initiation of the cell-cycle leads
to NE/NPC disassembly, a normal occurrence in mitotic cells. This hypothesis is based on our study of the six-transmembrane enzyme GDE2 (Glycerophosphodiester phosphodiesterase 2; GDPD5), which cleaves the GPI-(Glycosylphosphatidylinositol)-anchor that tethers some proteins to the plasma membrane. GDE2 is a potent
inhibitor of the mitotic cell-cycle and induces the differentiation of mitotic progenitors into post-mitotic neurons in
the developing nervous system. We discovered that in adult mice lacking GDE2 (Gde2 KO), cortical neurons
show evidence of cell-cycle re-entry, suggesting that GDE2 is required to preserve neurons in a quiescent state.
Strikingly, Gde2 KO neurons that have re-entered the cell-cycle show abnormal organization of the NE, aberrant
distribution of NPC proteins and impaired nucleocytoplasmic transport, raising the possibility that cell-cycle re-initiation and NE/NPC breakdown are linked. Consistent with this idea, genetic reduction of cyclin D, a critical
regulator of the G1/S transition, suppresses nucleocytoplasmic transport-dependent neurodegeneration in a
Drosophila model of c9ORF72 ALS-FTD. Notably, Gde2 KO mice display age-progressive neurodegeneration
and GDE2 distribution and function is disrupted in AD patient neurons. These observations suggest that
maintenance of neuronal quiescence is an active process and that failure of this process re-initiates the cell-cycle, triggers NE/NPC breakdown and induces neurodegeneration. Aim 1 will determine if GDE2 encodes a
new pathway that maintains neuronal quiescence and will determine if neuronal cell-cycle re-entry signals
NE/NPC breakdown in neurons. Preliminary RNAseq, analysis of Wnt-reporter mice in Gde2 KOs, and genetic
studies in Drosophila identify aberrant activation of canonical Wnt signaling as a candidate pathway that induces
neuronal cell-cycle re-entry, NE/NPC breakdown and neurodegeneration. Aim 2 will utilize mouse and
Drosophila models to test this hypothesis. Studies in Aim 3 will determine links between GDE2 dysfunction,
neuronal cell-cycle re-entry and NE/NPC breakdown in disease using Drosophila models of AD and ADRD,
human postmortem tissue and iPS human neurons. These studies will provide new molecu...

## Key facts

- **NIH application ID:** 10236490
- **Project number:** 5R01AG068043-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Thomas E. Lloyd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $656,416
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236490

## Citation

> US National Institutes of Health, RePORTER application 10236490, Neuronal cell-cycle re-entry and neurodegeneration (5R01AG068043-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10236490. Licensed CC0.

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