# Deconstructing the cellular and molecular basis of SBMA motor neuron disease: From mechanism to therapy

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $203,087

## Abstract

X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an inherited neuromuscular
disorder characterized by lower motor neuron degeneration. SBMA is caused by CAG/polyglutamine repeat
expansions in the human androgen receptor gene, and is one of nine neurodegenerative disorders that result
from polyglutamine (polyQ) proteins. We set out to determine the cellular and molecular basis of SBMA
disease pathogenesis. To achieve these goals, we created novel mouse models of SBMA, including BAC
transgenic mice containing a floxed first exon (i.e. the BAC fxAR121 line) to permit cell-type specific excision of
the AR transgene. We crossed BAC fxAR121 mice with Human Skeletal Actin (HSA)-Cre mice, and
documented that excision of the AR transgene from skeletal muscle prevented development of both systemic
and neuromuscular SBMA phenotypes, revealing a crucial role for muscle expression of mutant polyQ-AR in
SBMA motor neuron degeneration. We produced antisense oligonucleotides (ASOs) directed against AR, and
upon peripheral delivery, we demonstrated that peripheral suppression of polyQ-AR rescued motor deficits,
reversed alterations in muscle gene expression, and markedly extended lifespan in SBMA mice. These
provocative findings implicate skeletal muscle as a key site for SBMA disease pathogenesis. To determine the
contribution of motor neurons (MNs) to SBMA, we crossed BAC fxAR121 mice with vChAT-Cre mice, and
noted a modest, but significant improvement in motor performance in bigenic mice. Hence, SBMA disease
pathogenesis involves a convergence of alterations stemming from pathological interactions between skeletal
muscle and MNs. We also uncovered autophagy dysregulation as a defining feature of SBMA MN disease by
analyzing in vivo and in vitro models, including a human SBMA stem cell model. These studies revealed
abnormalities of autophagosome maturation and lysosome fusion in SBMA cell models, mice, and neuronal
progenitor cells derived from iPSCs, thereby linking autophagy dysfunction to the onset of SBMA. To delineate
the basis of this effect, we considered the transcriptional regulation of autophagy, uncovered an interaction
between AR and transcription factor EB (TFEB), and determined that TFEB dysregulation accounts for
autophagy defects in SBMA. In this project, we will define the molecular contributions of skeletal muscle and
MNs to SBMA by performing transcriptome analysis in our various conditional deletion SBMA mouse models;
delineate the cellular basis for MN demise by developing skeletal muscle and MN models of SBMA from
patient iPSCs, and determining if non-cell autonomous toxicity can be recapitulated in these stem cell models;
and define the basis for AR co-activation and polyQ-AR repression of TFEB by identifying co-regulators whose
interactions and functions with AR and TFEB in complex are altered in the presence of polyQ-AR.

## Key facts

- **NIH application ID:** 9973096
- **Project number:** 5R01NS100023-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** ALBERT R LA SPADA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,087
- **Award type:** 5
- **Project period:** 2016-09-30 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973096

## Citation

> US National Institutes of Health, RePORTER application 9973096, Deconstructing the cellular and molecular basis of SBMA motor neuron disease: From mechanism to therapy (5R01NS100023-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973096. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*