Journal
JOURNAL OF CELL SCIENCE
Volume 133, Issue 6, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.234047
Keywords
Endosomes; CLN3; Retromer; Sortilin; Juvenile neuronal ceroid lipofuscinosis; Rab7A
Categories
Funding
- EU Joint Programme in Neurodegenerative Diseases Grant (Neuronode)
- Canadian Institutes for Health Research [ENG-387575]
- Canadian Foundation for Innovation [35258]
- National Contest for Life Foundation Germany (NCL)
- Deutsche Forschungsgemeinschaft (DFG) [425373668, HE 3220/4-1]
- Fondation Universitaire Armand-Frappier scholarship
- Fond de Recherche du Quebec - Sante
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Mutations in CLN3 are a cause of juvenile neuronal ceroid lipofuscinosis (JNCL), also known as Batten disease. Clinical manifestations include cognitive regression, progressive loss of vision and motor function, epileptic seizures and a significantly reduced lifespan. CLN3 localizes to endosomes and lysosomes, and has been implicated in intracellular trafficking and autophagy. However, the precise molecular function of CLN3 remains to be elucidated. Previous studies showed an interaction between CLN3 and Rab7A, a small GTPase that regulates several functions at late endosomes. We confirmed this interaction in live cells and found that CLN3 is required for the efficient endosome-to-TGN trafficking of the lysosomal sorting receptors because it regulates the Rab7A interaction with retromer. In cells lacking CLN3 or expressing CLN3 harbouring a disease-causing mutation, the lysosomal sorting receptors were degraded. We also demonstrated that CLN3 is required for the Rab7A-PLEKHM1 interaction, which is required for fusion of autophagosomes to lysosomes. Overall, our data provide a molecular explanation behind phenotypes observed in JNCL and give an indication of the pathogenic mechanism behind Batten disease. This article has an associated First Person interview with the first author of the paper.
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