Pleiotrophin: a multifunctional regulator in neurodevelopment and neuropsychiatric diseases

Pleiotrophin (PTN) is a heparin-binding growth factor that plays a pivotal role in neurodevelopment, neuroplasticity, and neuroinflammation. PTN signals through a multi-receptor network involving protein tyrosine phosphatase receptor type ζ (PTPRZ1), syndecans (particularly syndecan-3), integrins, nucleolin, and neuropilin-1. Anaplastic lymphoma kinase (ALK) has also been functionally linked to PTN signaling, although whether PTN directly binds and activates it remains debated. This review comprehensively summarizes recent advances in understanding the structure, distribution, and multifunctional roles of PTN in the nervous system, with a particular focus on its involvement in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, anxiety, depression, and schizophrenia. Emerging evidence suggests that PTN exhibits context-dependent and often dual roles, both neuroprotective and pathogenic, depending on the disease stage and cellular microenvironment. This review highlights the potential of PTN as well as its receptors as therapeutic targets and underscores the direction for further research to elucidate its precise mechanisms in neurological and psychiatric conditions.