# Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice

## TL;DR

This study shows that Leigh syndrome, a mitochondrial disorder, causes early brain development issues in mice before neurodegeneration occurs.

## Contribution

The study reveals neurodevelopmental defects in a mouse model of Leigh syndrome prior to neurodegeneration, suggesting early developmental origins of the disease.

## Key findings

- Loss of Complex I disrupts neural stem cell proliferation and differentiation in the subventricular zone and corpus callosum.
- Myelin basic protein is reduced in a thinner corpus callosum, indicating impaired myelination.
- Neuroanatomic differences suggest delayed brain maturation in LS mice.

## Abstract

Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.

Leigh syndrome (LS) is the most common pediatric mitochondrial disorder. Neurodegenerative lesions eventually manifest in the brain as hallmark pathologies, yet LS patients often report neurodevelopmental delays. Using a mouse model of LS, the authors investigated the origin of these delays.

Diffuse neuroanatomic differences indicate delayed brain maturation.Neural stem progenitor cells display disruptions in proliferation, renewal, and differentiation capacity.Transcriptomics and histological profiling revealed dynamic changes across heterogeneous populations of neural stem cells and their neural/glial progeny.Myelin basic protein is reduced within a thinner corpus callosum while cortical thickness remains unchanged.

Diffuse neuroanatomic differences indicate delayed brain maturation.

Neural stem progenitor cells display disruptions in proliferation, renewal, and differentiation capacity.

Transcriptomics and histological profiling revealed dynamic changes across heterogeneous populations of neural stem cells and their neural/glial progeny.

Myelin basic protein is reduced within a thinner corpus callosum while cortical thickness remains unchanged.

Leigh syndrome (LS) is the most common pediatric mitochondrial disorder. Neurodegenerative lesions eventually manifest in the brain as hallmark pathologies, yet LS patients often report neurodevelopmental delays. Using a mouse model of LS, the authors investigated the origin of these delays.