# Microgliopathy as a primary mediator of neuronal death in models of Friedreich’s Ataxia

## TL;DR

This study shows that microglial dysfunction, caused by FXN deficiency, drives neurodegeneration in Friedreich’s ataxia and can be reversed with gene editing.

## Contribution

The paper identifies microglial dysfunction as a primary driver of neuronal death in Friedreich’s ataxia, offering a new therapeutic target.

## Key findings

- FXN deficiency in microglia leads to mitochondrial defects, iron overload, and inflammation.
- CRISPR/Cas9 correction of the GAA repeat reverses microglial defects and prevents neuronal loss.
- Human FRDA microglia transplanted into mice cause Purkinje neuron loss in healthy brains.

## Abstract

Friedreich’s ataxia (FRDA) is an incurable neurodegenerative disorder caused by a GAA repeat expansion in the frataxin (FXN) gene, leading to a severe reduction of the mitochondrial FXN protein, crucial for iron metabolism. While microglial inflammation is observed in FRDA, it remains unclear whether immune dysfunction is a primary disease mediator or a secondary reactionary phenotype. Utilizing patient-derived induced pluripotent stem cells (iPSCs), we report an intrinsic microglial phenotype of stark mitochondrial defects, iron overload, lipid peroxidation, and lysosomal abnormalities. These factors drive a pro-inflammatory state that contributes to neuronal death in co-culture systems. In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.

Friedreich’s ataxia (FRDA) is a neurodegenerative disorder driven by frataxin (FXN) deficiency. Here, the authors show that FXN loss in human microglia causes mitochondrial and lysosomal defects that trigger neuroinflammation and neurodegeneration, rescued by gene editing.