PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Abstract

Receptor‐type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive‐compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction‐related effects, and the implications of these findings for the PTPRD‐associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.

The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis

“…Here, we analyzed the role of the tyrosine phosphatase PTPRD in NPCs during embryonic cortical development. Ptprd, the gene that encodes this protein, is associated with several neurodevelopmental disorders, including obsessive-compulsive disorder, ASDs, and intellectual disability (Choucair et al, 2015;Uhl and Martinez, 2019). We show that Ptprd is a key determinant of embryonic neurogenesis, controlling the numbers of neurogenic intermediate progenitor cells and, ultimately, the number of cortical neurons.…”

“…Receptor protein tyrosine phosphatase delta (PTPRD), a member of the LAR (leukocyte common antigen-related receptor) family and a regulator of tyrosine kinase signaling, has been associated with several neural disorders (Choucair et al, 2015;Uhl and Martinez, 2019). However, its function and contribution to neural development and the pathogenesis of neural disorders has not yet been studied.…”

Splice‐dependent trans‐synaptic PTP δ– IL 1 RAPL 1 interaction regulates synapse formation and non‐ REM sleep

“…PTPδ has been implicated in various brain disorders, including ADHD, restless leg syndrome, addiction, bipolar disorder, obsessive–compulsive disorder, and intellectual disability (Anney et al , ; Schormair et al , ; Elia et al , ; Distel et al , ; Malhotra et al , ; Yang et al , ; Kim et al , ; Jarick et al , ; Moore et al , ; Choucair et al , ; Drgonova et al , ; Mattheisen et al , ; Uhl et al , ; Uhl & Martinez, ). Our results indicate that hyperactivity and sleep disturbances are shared by Ptprd −/− , Emx1‐Cre;Ptprd fl / fl , and Ptprd‐meA −/− mice (Fig ).…”

“…Beyond these fundamental aspects, LAR‐RPTPs have been implicated in diverse brain disorders. In particular, PTPRD has been extensively associated with a large number of brain disorders (Uhl & Martinez, ), including attention‐deficit hyperactivity disorder (ADHD) (Anney et al , ; Elia et al , ; Distel et al , ; Jarick et al , ), restless leg syndrome (SNP study) (Schormair et al , ; Yang et al , ; Kim et al , ; Moore et al , ), addiction (Drgonova et al , ; Uhl et al , ), bipolar disorder (Malhotra et al , ), obsessive–compulsive disorder (Mattheisen et al , ), and intellectual disability (Choucair et al , ). Previous studies on Ptprd ‐mutant mice have revealed impairments in synaptic plasticity, learning, and memory (Uetani et al , ; Drgonova et al , ); dendritic arborization in cortical neurons (Nakamura et al , ); and axon targeting in motor neurons (Uetani et al , ), as well as enhanced cocaine preference and suppressed sleep‐like behaviors (Drgonova et al , ).…”

Diverse phenotypic measurements of wellbeing: Heritability, temporal stability and the variance explained by polygenic scores

“…Similarly, there is evidence for the involvement of PTPRD variants in correlated behavioral phenotypes such as loneliness, 32 temperament, 33 openness, 34 anxiety and major depression 35 . PTPRD is expressed most abundantly in brain tissue, and has a role as a neuronal cell adhesion molecule and synaptic specifier, 36 making it a good candidate for wellbeing and related behavioral traits and psychopathology.…”