Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase

PLoS Genet. 2017 Feb 21;13(2):e1006621. doi: 10.1371/journal.pgen.1006621. eCollection 2017 Feb.

Abstract

Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported in the same transport vesicle? Is active zone protein transport regulated? In this report we show that overexpression of Par-1/MARK kinase, a protein whose misregulation has been implicated in Autism spectrum disorders (ASDs) and neurodegenerative disorders, lead to a specific block in the transport of an active zone protein component- Bruchpilot at Drosophila neuromuscular junctions. Consistent with a block in axonal transport, we find a decrease in number of active zones and reduced neurotransmission in flies overexpressing Par-1 kinase. Interestingly, we find that Par-1 acts independently of Tau-one of the most well studied substrates of Par-1, revealing a presynaptic function for Par-1 that is independent of Tau. Thus, our study strongly suggests that there are distinct mechanisms that transport components of active zones and that they are tightly regulated.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Axons / metabolism
  • Drosophila
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Glycogen Synthase Kinase 3 / genetics*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Neuromuscular Junction / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / pathology
  • Protein Transport / genetics
  • Synapses / genetics
  • Synapses / pathology
  • Synaptic Transmission / genetics
  • tau Proteins / genetics*

Substances

  • BRP protein, Drosophila
  • Drosophila Proteins
  • tau Proteins
  • Glycogen Synthase Kinase 3
  • Par-1 protein, Drosophila

Grants and funding

This work was supported by STARS award from the University of Texas system, startup funds from the University of Texas Medical Branch to YPW, the Mitchell Center for Neurodegenerative Diseases, John Sealy Memorial Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.