CLN3 regulates endosomal function by modulating Rab7A activity

Abstract

Mutations in CLN3 are a cause of juvenile NCL (JNCL), also known as Batten Disease.Clinical manifestations includes 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. We show that CLN3 interacts with Rab7A, a small GTPase that regulates several functions at late endosomes. We found that CLN3 is required for the efficient endosome-to-TGN trafficking of the lysosomal sorting receptors by regulating the Rab7A/retromer interaction. 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 autophagosome/lysosome fusion. Overall, our data provides a molecular explanation behind phenotypes observed in JNCL.

Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease

“…Various neuronal deficits have been shown in in vitro models of the disease, including increased susceptibility to glutamatergic excitotoxicity (Kovacs et al, 2006;Finn et al, 2011), alterations in synaptic plasticity (Grünewald et al, 2017;Studniarczyk et al, 2018), impaired synaptogenesis (Gomez-Giro et al, 2019), and network dysfunction (Ahrens-Nicklas et al, 2019;Ahrens-Nicklas et al, 2022), but none of these have been linked directly to a molecular function for the protein. A recent study demonstrated that CLN3 regulates the retromer-dependent recycling of lysosomal sorting receptors (Yasa et al, 2020;Yasa et al, 2021), which could prove to be an important development for the field (Cotman and Lefrancois, 2021).…”