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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.

American Journal of Human Genetics
|April 18, 2017
PubMed

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.

Keywords:
Phospholipase A2-activating proteinUfd3autophagycerebellumendolysosomal traffickingmicrocephalyseizuressynapsesynaptic vesicle recyclingubiquitin

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