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4-hydroxymandelate acid or astrocyte specific gene therapy is sufficient to rescue a hpdl-related neurometabolic disease

ABSTRACT: Biallelic mutations in HPDL cause a rare form of infantile-onset mitochondrial encephalopathy, yet the mechanisms underlying disease pathogenesis remain poorly understood. Here, we show that Hpdl-deficient mice exhibit early lethality, seizures, impaired brain development, and coenzyme Q deficiency. Astrocyte-specific Hpdl deletion recapitulated key metabolic and structural abnormalities, indicating a central role for glial dysfunction. Single-nucleus RNA sequencing identified disease-associated astrocyte subpopulations with reactive signatures, impaired glutamate transport, and transcriptional dysregulation linked to energy failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE303429 | GEO | 2026/07/01

REPOSITORIES: GEO

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