A novel non-human primate model of Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases. •Neonatal rhesus macaques (RM) with PLP1 mutations develop motor and other symptoms.•PLP1 mutant animals resemble human patients with Pelizaeus-Merzbacher disease (PMD).•RM-PMD is characterized by hypomyelination, astrogliosis, and microglial activation.•Oligodendrocyte progenitor cell proliferation and apoptosis are elevated in RMPMD white matter.•RM-PMD is a novel non-human primate model of PMD.