2. Academic Validation
  3. CLN3 mediates chloride efflux from lysosomes

CLN3 mediates chloride efflux from lysosomes

  • Neuron. 2026 Mar 4;114(5):868-883.e7. doi: 10.1016/j.neuron.2025.11.013.
Yayu Wang 1,  Kai Li 1,  Wei Chen 1,  Chao Chen 1,  Adeline J H Yong 1,  Xiaofan Zhang 1,  Marena Tynan-La Fontaine 1,  Yuh Nung Jan 1,  Lily Yeh Jan 2
Affiliations

Affiliations

  • 1 Department of Physiology, University of California at San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA.
  • 2 Department of Physiology, University of California at San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID: 41558486 DOI: 10.1016/j.neuron.2025.11.013
Abstract

Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible Materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders.

Keywords

Batten disease; CLN3; chloride channel; lysosome; neurodegenerative disease.

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