簡介:
- 作者: Masood Ahmad Wani, Chloe M. Hall, Thomas Mittmann, Benedikt Grünewald, Jakob von Engelhardt
- 雜志: BioRxiv
- Doi: https://www.doi.org/10.1101/2025.11.12.687979
- 出版日期: 2025/11/12
摘要
Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease) is a childhood-onset, neurodegenerative, lysosomal storage disorder caused by mutations in the lysosomal gene CLN3. Progressive cognitive decline is a key clinical manifestation of JNCL, and no definitive treatment is currently available. The precise function of CLN3 in neurons remains unclear, hindering the development of targeted therapies. Using patch-clamp and AAV-mediated re-expression of CLN3 in Cln3Δex7/8 mice, we demonstrate that CLN3 is essential for synaptic function. Loss of CLN3 caused defective synaptic vesicle release and reduced synaptic strength reflecting impairments in both pre- and postsynaptic function in Cln3Δex7/8 mice before the occurrence of neurodegeneration. Moreover, we observed reduced network bursting and deficits in intrinsic neuronal excitability, indicating early functional disturbances independent of storage burden and neuronal death in Cln3-deficient mice. To assess whether CLN3 is required for proper pre- and postsynaptic function, we re-expressed CLN3 selectively in pre- and postsynaptic neurons. We found non-redundant requirements at both pre- and postsynaptic sites to sustain function. Importantly, AAV9-mediated gene rescue at early-disease stages corrected preexisting synaptic defects and restored function. Together, these findings demonstrate the requirement of CLN3 in maintaining synaptic function and show that the therapeutic window may extend to stages characterized by early functional deficits, highlighting the potential of targeted gene therapy to restore function and improve cognitive outcomes.
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