Pleiotrophin/Midkine Pathway Is Dysregulated in a TDP ‐ 43 A315T Mouse Model of Amyotrophic Lateral Sclerosis ( ALS )

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by progressive degeneration of both upper and lower motor neurons, along with skeletal muscles innervated by them. The identification of key molecules involved in disease pathology remains crucial for ALS, as no curative treatment is currently available. Pleiotrophin (PTN) and midkine (MK) are closely related, heparin‐binding cytokines with overlapping effects. These molecules have been shown to be neuroprotective by modulating neuroinflammation, supporting neuronal survival, growth, and differentiation, and enhancing synaptic strength and plasticity. Despite their reported neuroprotective properties, the involvement of PTN and MK signaling in ALS has not been previously investigated. In this study, we characterized the expression of the PTN/MK pathway in the lumbar spinal cords (SCs) of TDP‐43 A315T mice across different disease stages. We report a significant upregulation of Ptn , Mdk , and its receptor protein tyrosine phosphatase zeta ( Ptprz1 ) mRNA levels at end‐stage of disease in the lumbar SC of TDP‐43 A315T mice compared with age‐matched wild‐type littermates. Protein levels of PTN and MK were also upregulated at end‐stage of disease. By immunofluorescence analysis, we also observed an upregulation of the immunostaining of both cytokines in neurons, astrocytes, microglia, and pericytes‐like structures at end‐stage of disease in the SC of TDP‐43 A315T mice. These findings open a new avenue to further study the potential role of the PTN/MK signaling axis in the pathogenesis of ALS. Trial Registration: Animal Ethics Committee of the Hospital Nacional de Parapléjicos in Toledo (Spain): Approval No. 26/OH 2018