Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain.

Shu-Yin Xu,Xiao-Xin Yan,Qi Zhang,Aihua Pan,Juan Jiang,Lily Wan,Jim Manavis,Qi-Lei Zhang,Tian Tu,Yan Cai

doi:10.3389/fnana.2019.00031

Abstract

Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II–VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II–VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

Highlights

Sortilin was originally purified via receptor-associated affinity chromatography from human brain extracts and characterized as a type I transmembrane protein belonging to the vacuolar protein sorting 10 protein (VPS10P) domain receptor family (Petersen et al, 1997)
For a given neuroanatomical region, low magnification figures will demonstrate the overall distribution of the labeling, while high magnification illustrations depict the detailed morphology of the labeled cells
We further report a correlation between somal size and immunolabeling intensity among labeled neurons in the amygdala and cerebral cortex based on quantitative analyses

Summary

Introduction

Sortilin was originally purified via receptor-associated affinity chromatography from human brain extracts and characterized as a type I transmembrane protein belonging to the vacuolar protein sorting 10 protein (VPS10P) domain receptor family (Petersen et al, 1997). Many signaling proteins have been identified as sortilin ligands in the central and peripheral systems (Mazella et al, 1998; Nykjaer and Willnow, 2012; Quistgaard et al, 2014; Xu et al, 2018). Sortilin may involve in mood disorders (Buttenschøn et al, 2015; Devader et al, 2017; Moreno et al, 2018), and in brain aging and Alzheimer’s disease (AD) pathogenesis by interplaying with β-amyloid precursor protein (APP), β-secretase-1 (BACE1) and tau (Finan et al, 2011; Gustafsen et al, 2013; Yang et al, 2013; Andersson et al, 2016; Johnson et al, 2017; Xu et al, 2018). Sortilin may sort/transport protein products into the lysosomal system, which is key to intracellular protein homeostasis but might be relevant to the occurrence of intraneuronal proteinopathies (Canuel et al, 2009; Dumaresq-Doiron et al, 2013; Zhou et al, 2015; Paushter et al, 2018; Zhou X. et al, 2018)

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Conclusion