# CLN7 protein functions at the interface between endolysosomes and stress granules to promote cell survival

## TL;DR

This study explores how the CLN7 protein helps cells survive stress by connecting endolysosomes and stress granules, and how its loss causes neurodegenerative disease.

## Contribution

The study reveals CLN7's dual role in endolysosomal transport and stress granule interactions, linking its dysfunction to neurodegeneration.

## Key findings

- CLN7 loss causes lysosomal dysfunction and reduced mitophagy in neural progenitor cells.
- CLN7 interacts with stress granules, affecting RNA processing and nuclear export.
- Loss of CLN7 leads to neuronal apoptosis in Batten disease.

## Abstract

Inherited biallelic mutations in the CLN7 gene result in the variant late infantile onset neuronal ceroid lipofuscinosis, a subtype of Batten disease (BD), a severe and fatal childhood neurodegenerative disease. Intriguingly, CLN7 genetic variants have also been associated with retinopathies, amyotrophic lateral sclerosis, and frontotemporal dementia. CLN7 encodes a transmembrane protein localizing to endolysosomal membranes with outward-facing chloride channel activity. Loss of CLN7 function results in cortical neurons accumulating swollen lipofuscin-containing lysosomes, leading to neuroinflammation and neurodegeneration. The molecular mechanisms underlying CLN7 BD neuropathology are not completely understood. We have generated iPSC lines from two CLN7 BD patients and age-matched unaffected controls to interrogate intracellular molecular phenotypes in iPSC-derived neural progenitor cells (iNPC). Taking a multi-omics approach we have identified disease-modified activities in endolysosomal transport in iNPCBD that lead to lysosomal dysfunction and decreased mitophagy, resulting in the accumulation of metabolically defective mitochondria. We further observe a breakdown in nuclear functions that centre on RNA processing and nuclear export, linking to CLN7 protein interactions at the stress granule. We have identified dual and distinct functions for CLN7, promoting cell survival during the cellular stress response. CLN7 loss of function in BD results in neuronal apoptosis.