# Brain organoid models of Huntington's disease shift the focus towards neurodevelopment

## TL;DR

This paper shows that Huntington's disease may start affecting brain development early, suggesting early treatments could delay or prevent the disease.

## Contribution

The study uses brain organoids to reveal early developmental disruptions caused by mutant huntingtin in Huntington's disease.

## Key findings

- Mutant huntingtin impairs neural progenitor organization and function in brain organoids.
- Early developmental disruptions are linked to mitochondrial stress in Huntington's disease models.
- Improving mitochondrial health may help delay disease onset in Huntington's disease.

## Abstract

Huntington's disease (HD) is traditionally viewed as an age-related disorder. Emerging evidence suggests that mutant huntingtin (mHTT) disrupts early neurodevelopment, although the contribution of developmental alterations to the late disease onset remains to be clarified. Leveraging human pluripotent stem cell-derived brain organoids, we and others are exploring how mHTT affects the developing human brain. These models reveal impaired neural progenitor organization and function, accompanied by a mitochondrial stress response, indicating reduced capacity to manage cellular stress. Enhancing mitochondrial health and promoting neural cell resilience may thus represent potential strategies for improving the brain's compensatory mechanisms, thereby prolonging a healthy state. These insights highlight a potential window of opportunity for therapeutic interventions. Targeting mitochondrial fitness and neurodevelopmental pathways at early stages – long before clinical symptoms emerge – could help prevent or delay disease onset and progression in affected individuals.

Summary: Increasing evidence indicates neurodevelopmental aspects in Huntington's disease. Early interventions promoting healthy brain development and mitochondrial fitness might lead to prevention or delay of the disease pathology.