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.

Keywords: addiction; cell adhesion molecule; cocaine; neurofibrillary tangles; neurotherapeutics; obsessive compulsive disorder; restless leg syndrome.

Figure 1.

PTPRD domains. Immunoglobulin (IG, with miniexons (Me) A and B shown), fibronectin type III (FN), transmembrane (TM), active tyrosine phosphatase domain (D1), and enzymatically inactive regulatory domain (D2). Upper right: structure of the complex between the PTPRD IG and first FN domains with the leucine-rich repeat region of SLITRK2. Lower right: D1 domain dephosphorylation of phosphotyrosine 705 in STAT3, an example of PTPRD activity.

Figure 2.

Associations at PTPRD locus (top) and PTPRD introns (bottom) (Manhattan plot). Diamonds: –log P values for addiction-related phenotypes: smoking cessation success (blue; Uhl et al., unpublished observations) and positive responses to amphetamine (orange; data kindly provided by A. Hart). Filled circles: Intron positions of SNPs most strongly associated with RLS (green), levels of brain PTPRD mRNA expression (red), and neurofibrillary tangle density in Alzheimer’s disease brains (purple), and positions of SNPs most strongly associated with mood lability (orange) and obsessive-compulsive disorder (black). Left is telomeric and 3’, including the most 3’ exon encoding the 3’ untranslated region. Right: 5’ exons 1–12 encode the 5’ untranslated region of common adult brain transcripts.

Figure 3.

Heterozygous Ptprd knockout mice display reduced cocaine-conditioned place preference (top), cocaine self-administration (middle, fixed ratio 1 schedule) and sleep (bottom, 2h around “lights on”). Homozygotes display larger sleep deficits than heterozygotes. All differences are statistically significant.

Figure 4.

Structure of the first PTPRD phosphatase inhibitor 7-BIA (7-butoxy illudalic acid analog).

Figure 5.

7-BIA pretreatment reduces cocaine-conditioned place preference (top) and self-administration (bottom) in wild-type but not Ptprd knockout (KO) mice.