# Neurodegenerative mechanisms in Christianson syndrome and NHE6-related disorders

> **NIH NIH R01** · BROWN UNIVERSITY · 2020 · $948,191

## Abstract

PROJECT SUMMARY
Human genetics offers a powerful approach to dissect cellular mechanisms in neurodegenerative disease. We
are studying new genetic conditions with neurodegeneration caused by mutations in the X-linked endosomal
Na+/H+ exchanger 6 (NHE6, also known as SLC9A6). Dysfunction of the endolysosomal system is a common
feature in many neurodegenerative disorders. Loss-of-function mutations in NHE6 in males cause Christianson
syndrome (CS), which displays mixed neurodevelopmental and neurodegenerative pathology. My research
group has recently discovered adult-onset, neurodegenerative disease in female NHE6 mutation carriers. Data
in NHE6-related disease support pathology, including axonal degeneration, cerebellar degeneration, and
diffuse tau-related disease. The objective of the research in this R01 proposal is to define the cellular
mechanisms that cause NHE6-related neurodegeneration, as well as to develop mechanistic linkages to other
related neurodegenerative disorders, including Alzheimer’s disease (AD) and AD-related dementias (ADRD).
Our central hypothesis is that loss of NHE6 leads to abnormal maturation of late endosomes, thereby causing
aberrant retrograde axonal transport and lysosomal dysfunction. My research group, with our collaborators, is
in an excellent position to study NHE6-related neurologic disease, both in males and females, as we have
developed unique resources including: an international patient registry with patient phenotypic information; the
mouse Nhe6 conditional mutant; a panel of patient-derived iPSC cells with robust controls; and an Nhe6-null
rat model. We capitalize on the relative strengths of each experimental model to address our scientific
questions. We will pursue the following Specific Aims: 1) Demonstrate that neuronal, cell-autonomous loss of
NHE6 function in the mature brain causes neurodegeneration; 2) Determine the mechanism by which loss of
NHE6 leads to aberrant endosome maturation, lysosomal function, and retrograde axonal transport; and 3)
Determine the extent to which impairments in neuronal connectivity in NHE6-null neurons are mediated by tau-
related mechanisms. In these Aims, we study mechanisms in CS, as well as neurodegenerative mechanisms
in the female-specific NHE6-related syndrome. This research will have a sustained impact on both
fundamental neuronal cell biology and on translational neuroscience. These studies will define the
neurodegenerative mechanisms in new genetic diseases in males and females, and will establish linkages with
more common neurodegenerative disorders, potentially identifying new therapeutic targets. Additionally, our
research uses a powerful integrated translational approach, bridging patient-oriented studies to experimental
models. Finally, we are establishing valuable experimental resources for these studies, which we will share
broadly in order to maximize their utility for the research community.

## Key facts

- **NIH application ID:** 10020810
- **Project number:** 5R01NS113141-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Eric M Morrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $948,191
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020810

## Citation

> US National Institutes of Health, RePORTER application 10020810, Neurodegenerative mechanisms in Christianson syndrome and NHE6-related disorders (5R01NS113141-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020810. Licensed CC0.

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