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PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by Disrupting Ubiquitin-Mediated Endolysosomal
Emma A Hall1, Michael S Nahorski2, Lyndsay M Murray3
1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Insights
Synaptic proteostasis relies on the endolysosomal pathway, not just the ubiquitin-proteasome system. Mutations in PLAA disrupt this pathway, leading to neurodysfunction and impaired synaptic vesicle recycling.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Synaptic function relies on precise protein turnover, with the ubiquitin-proteasome system (UPS) traditionally considered central to synaptic proteostasis.
- Ubiquitin signaling plays a critical role at synapses, but the specific pathways for synaptic protein degradation remain incompletely understood.
Purpose of the Study:
- To investigate the role of the endolysosomal pathway in synaptic proteostasis and neurotransmission.
- To elucidate the function of the ubiquitin adaptor protein PLAA in neuronal development and synaptic function.
Main Methods:
- Characterization of human and mouse models with hypomorphic mutations in the PLAA gene.
- Analysis of protein accumulation, specifically K63-polyubiquitylated proteins and synaptic membrane proteins, in mutant neurons.
- Assessment of synaptic vesicle recycling and neurotransmission in the context of perturbed endolysosomal degradation.
Main Results:
- Mutations in PLAA lead to an infantile-lethal neurodysfunction syndrome characterized by seizures.
- Plaa mutant neurons exhibit impaired endolysosomal degradation, resulting in the accumulation of K63-polyubiquitylated proteins and synaptic membrane proteins.
- Disruption of endolysosomal trafficking in Plaa mutants severely impairs synaptic vesicle recycling and neurotransmission.
Conclusions:
- The endolysosomal pathway is essential for the turnover of synaptic membrane proteins and overall synaptic function.
- PLAA is a critical ubiquitin adaptor protein involved in mediating endolysosomal degradation at the synapse.
- Dysfunctional ubiquitin-mediated endolysosomal trafficking underlies a severe neurological disorder, highlighting its importance in neural health.
Abstract:
During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function. In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. Resulting from perturbed endolysosomal degradation, Plaa mutant neurons accumulate K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Through characterization of this neurological intracellular trafficking disorder, we establish the importance of ubiquitin-mediated endolysosomal trafficking at the synapse.