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

• Published in: Annals of the New York Academy of Sciences Vol. 1451; no. 1; pp. 112 - 129
• Main Authors: Uhl, George R., Martinez, Maria J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2019
• Subjects: addiction; Addictions; Alzheimer's disease; Animal models; Animals; Behavior, Addictive - genetics; Behavior, Addictive - metabolism; Brain; Brain - metabolism; Cell adhesion; Cell adhesion & migration; cell adhesion molecule; Cell adhesion molecules; cocaine; Cognitive ability; Disease Models, Animal; Genetics; Genomics; Humans; Lability; Mood; Nervous system; Neurobiology; Neurodegenerative diseases; neurofibrillary tangles; Neurosciences; neurotherapeutics; obsessive compulsive disorder; Pharmacology; Phenotype; Phenotypes; Phosphatase; Polymorphism, Single Nucleotide; Protein-tyrosine-phosphatase; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - metabolism; restless leg syndrome; Tyrosine; cocaine; restless leg syndrome; addiction; neurofibrillary tangles; cell adhesion molecule; neurotherapeutics; obsessive compulsive disorder
• ISSN: 0077-8923; 1749-6632; 1749-6632
• DOI: 10.1111/nyas.14002

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. Receptor‐type protein tyrosine phosphatase, receptor type D (PTPRD) is a neuronal cell adhesion molecule and synaptic specifier that has possible roles in addiction, Alzheimer's disease, cognitive impairment, mood lability, and obsessive‐compulsive disorder. This article reviews PTPRD's discovery, gene family, candidate binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes.