SORLA regulates calpain-dependent degradation of synapsin

Alzheimers Dement. 2016 Sep;12(9):952-963. doi: 10.1016/j.jalz.2016.02.008. Epub 2016 Mar 25.

Abstract

Introduction: Sorting-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor in neurons and a major risk factor for Alzheimer disease.

Methods: Here, we performed global proteome analyses in the brain of SORLA-deficient mice followed by biochemical and histopathologic studies to identify novel neuronal pathways affected by receptor dysfunction.

Results: We demonstrate that the lack of SORLA results in accumulation of phosphorylated synapsins in cortex and hippocampus. We propose an underlying molecular mechanism by demonstrating that SORLA interacts with phosphorylated synapsins through 14-3-3 adaptor proteins to deliver synapsins to calpain-mediated proteolytic degradation.

Discussion: Our results suggest a novel function for SORLA which is in control of synapsin degradation, potentially impacting on synaptic vesicle endocytosis and/or exocytosis.

Keywords: Alzheimer's disease; Risk factor; SORLA; Sorl1; Sporadic AD; Synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Alzheimer Disease
  • Animals
  • Calpain / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Male
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / genetics
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • Proteolysis
  • Proteome*
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Synapsins / metabolism*

Substances

  • 14-3-3 Proteins
  • Membrane Transport Proteins
  • Proteome
  • Receptors, LDL
  • Sorl1 protein, mouse
  • Synapsins
  • Calpain