SORLA regulates calpain‐dependent degradation of synapsin

Abstract

IntroductionSorting‐related receptor with A‐type repeats (SORLA) is an intracellular sorting receptor in neurons and a major risk factor for Alzheimer disease.MethodsHere, 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.ResultsWe 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.DiscussionOur results suggest a novel function for SORLA which is in control of synapsin degradation, potentially impacting on synaptic vesicle endocytosis and/or exocytosis.

The Role of Synapsins in Neurological Disorders

“…It interacts strongly with phospho-synapsins I and II and subsequently promotes their degradation by the protease calpain. However, a loss of synapsin-SORLA interaction results in the accumulation of phosphorylated synapsins in the cortex and hippocampus, thereby contributing to synaptic dysfunction in AD [39].…”

“…In addition to their involvement in the conditions discussed above, synapsins have also been linked to conditions like amyotrophic lateral sclerosis (ALS), autism [90], and hyperalgesia [91]. An immunohistochemical investigation of synaptic proteins has revealed differential expression between the two groups of synaptic proteins in the ALS anterior horn of the spinal cord where synaptic vesicle [36] Protein Interactions Synapsin interactions with SORLA in AD [39] Gene mutations PS-1 mutation in AD [40], Synapsin I and II mutations in epilepsy [50][51][52][53], Synapsin II and III mutations in schizophrenia [63][64][65][66][67][68][69][70] Altered epigenetic mechanisms Increased histone modification and decreased promoter DNA methylation in BD [76,77] Immunogenicity Synapsin-specific T cells in MS pathogenesis [82][83][84][85] Post-translational modifications Impaired phosphorylation in HD [88,89], Impaired sumoylation in epilepsy and autism [90] proteins including synapsin I are significantly decreased [92]. In addition, proteomic analysis of the spinal cord in a mouse model of ALS showed under-expression of synapsin II [93].…”

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

“…Presynaptically, Sorla can interact with phosphorylated synapsin, via 14-3-3 adaptor proteins to sort it for degradation by the protease calpain (Hartl et al, 2016). Also, supporting a role for Sorla in regulating synapsin turnover, a proteomic study of cortices and hippocampus of SORL1-deficient mice revealed an increase in synapsin 1 and 2 (Hartl et al, 2016).…”

“…Even in mild cognitive impairment, there is less Sorla expression (Sager et al, 2007). Sorla expression is widespread in the brain (Motoi et al, 1999) and localizes to early endosomes and Golgi compartments (Andersen et al, 2005;Offe et al, 2006) as well as pre-and postsynaptic compartments (Rohe et al, 2013;Hartl et al, 2016). SORL1's role in synaptic function is unclear.…”

The role of Alzheimer's disease risk genes in endolysosomal pathways

“…Synapsins are a family of proteins that are involved with the regulation of neurotransmitter release at synapses, and thus are essential in the processes of endo- and exocytosis. Deletion of SORLA in mice resulted in an accumulation of phosphorylated synapsins in various regions of the brain, indicating that SORLA may have a direct effect on the degradation of synapsins, which, in turn, could impact on synaptic vesicle endocytosis ( Hartl et al, 2016 ). Additionally, Huang and colleagues used SORLA transgenic mice to demonstrate an interaction with the ephrin receptor EphA4, which is important for synaptic structure and function( Huang et al, 2017 ).…”