# Molecular mechanisms of a neurodevelopmental seizure disorder

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $204,688

## Abstract

Project Summary
Disrupting neurodevelopmental processes leads to a range of neurological, psychiatric and behavioral
disorders. In the US, one in six children exhibit some form of neurodevelopmental disorder, ranging from
severe dysfunction to mild social-behavioral difficulties. Genetics plays a critical role and many genes have
been implicated as risk factors for diverse neurodevelopmental disorders. However, common themes that are
shared by multiple neurodevelopmental disorders include disturbances to the autophagy-lysosome pathway
and the dysregulation of mTORC1 kinase signaling. A common co-morbidity of neurodevelopmental disorders
with mutations affecting the autophagy-lysosome pathway and mTORC1 dysregulation are seizures, implying
that these fundamental cellular processes also underlie an imbalance in excitatory and inhibitory activities. The
goal of this project is to uncover a new molecular connection between the autophagy-lysosome pathway and
mTORC1 dysregulation that leads to neurodevelopmental disorders and epilepsy. In yeast we found that the
yeast Kctd (Whi2 protein/Whi2p) is a potent negative regulator of TORC1 and is required for induction of
autophagy in low nutrient conditions. Based on findings from yeast models, we identified mammalian
counterparts as a family of understudied human genes known as the potassium channel tetramerization
domain proteins (KCTDs). The long-established binding partners of yeast Kctd (Whi2) are the yeast protein
phosphatases Psr1 and Psr2, which have obvious human homologs, the CTDSP/CSP phosphatase family. We
will test the hypothesis that KCTD family proteins are regulators of a protein quality control pathway that is also
connected to the mTORC1 signaling pathway. Several KCTD family members have been linked to
neurodevelopmental disorders including epilepsies, autism and schizophrenia. We propose to translate our
unique insights gained from studies in yeast to delineate an important molecular mechanism of pathogenesis in
the brain using cellular and biochemical approaches and a mouse model that recapitulates important aspects
human disease.

## Key facts

- **NIH application ID:** 10433302
- **Project number:** 1R21NS127076-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** J. Marie Hardwick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $204,688
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433302

## Citation

> US National Institutes of Health, RePORTER application 10433302, Molecular mechanisms of a neurodevelopmental seizure disorder (1R21NS127076-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433302. Licensed CC0.

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