Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway
Parkinson's Disease (PD) is characterized by midbrain dopaminergic (mDA) neuron degeneration in the ventral midbrain, contributing to debilitating motor symptoms. This study investigated whether Protein Tyrosine Phosphatase Receptor Sigma (PTPRS), a known inhibitor of axonal growth through chon...
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Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002396 |
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| author | Joshua Peter Kaejaren C.N. Caldwell Lucas McClain Jason Tchieu Ashley E. Ross Yu Luo |
| author_facet | Joshua Peter Kaejaren C.N. Caldwell Lucas McClain Jason Tchieu Ashley E. Ross Yu Luo |
| author_sort | Joshua Peter |
| collection | DOAJ |
| description | Parkinson's Disease (PD) is characterized by midbrain dopaminergic (mDA) neuron degeneration in the ventral midbrain, contributing to debilitating motor symptoms. This study investigated whether Protein Tyrosine Phosphatase Receptor Sigma (PTPRS), a known inhibitor of axonal growth through chondroitin sulfate proteoglycan (CSPG) interaction, plays a role in mDA neuron survival, function, and regeneration in PD. Our data show that inhibition of PTPRS using intracellular sigma peptide (ISP) enhances human mDA neuron neurite outgrowth in vitro, suggesting an inhibitory role of this receptor in the differentiation of human embryonic stem cell (hESC)-derived mDA neurons in vitro. However, genetic deletion and pharmacological inhibition of PTPRS does not affect mDA neuron survival, axon density, or motor behavior in 6-OHDA unilateral partially lesioned mice. Similarly, mDA-specific deletion of Ptprs does not affect the basal behavioral measurement in cKO mice, including general locomotion and motor learning. Interestingly, however, Ptprs deletion led to a reduced response in the behavior sensitization to repeated methamphetamine (METH) exposure in cKO mice, suggesting a dampened response in synaptic function in cKO mice under these conditions. Ex vivo voltammetry recording in the striatum indeed shows altered parameters of dopamine (DA) release upon stimulation. These findings indicate that the inhibition of PTPRS function in human mDA neuron progenitors might be a promising strategy for enhancing neurite outgrowth or incorporation in host tissues in transplantation therapies. Finally, our data support that inhibition of PTPRS function in mDA neurons in adult mice in vivo could inhibit METH induced plasticity and behavioral sensitization. |
| format | Article |
| id | doaj-art-ab781b83ec274effb85d64cf34b8fca9 |
| institution | DOAJ |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-ab781b83ec274effb85d64cf34b8fca92025-08-20T02:45:42ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310702310.1016/j.nbd.2025.107023Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathwayJoshua Peter0Kaejaren C.N. Caldwell1Lucas McClain2Jason Tchieu3Ashley E. Ross4Yu Luo5Department of Molecular and Cellular Biosciences, University of Cincinnati, Cincinnati, OH 45229, USANeuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45229, USADepartment of Molecular and Cellular Biosciences, University of Cincinnati, Cincinnati, OH 45229, USADivision of Developmental Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USADepartment of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USADepartment of Molecular and Cellular Biosciences, University of Cincinnati, Cincinnati, OH 45229, USA; Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45229, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Corresponding author at: Department of Molecular and Cellular Biosciences, University of Cincinnati, Cincinnati, OH 45229, USA.Parkinson's Disease (PD) is characterized by midbrain dopaminergic (mDA) neuron degeneration in the ventral midbrain, contributing to debilitating motor symptoms. This study investigated whether Protein Tyrosine Phosphatase Receptor Sigma (PTPRS), a known inhibitor of axonal growth through chondroitin sulfate proteoglycan (CSPG) interaction, plays a role in mDA neuron survival, function, and regeneration in PD. Our data show that inhibition of PTPRS using intracellular sigma peptide (ISP) enhances human mDA neuron neurite outgrowth in vitro, suggesting an inhibitory role of this receptor in the differentiation of human embryonic stem cell (hESC)-derived mDA neurons in vitro. However, genetic deletion and pharmacological inhibition of PTPRS does not affect mDA neuron survival, axon density, or motor behavior in 6-OHDA unilateral partially lesioned mice. Similarly, mDA-specific deletion of Ptprs does not affect the basal behavioral measurement in cKO mice, including general locomotion and motor learning. Interestingly, however, Ptprs deletion led to a reduced response in the behavior sensitization to repeated methamphetamine (METH) exposure in cKO mice, suggesting a dampened response in synaptic function in cKO mice under these conditions. Ex vivo voltammetry recording in the striatum indeed shows altered parameters of dopamine (DA) release upon stimulation. These findings indicate that the inhibition of PTPRS function in human mDA neuron progenitors might be a promising strategy for enhancing neurite outgrowth or incorporation in host tissues in transplantation therapies. Finally, our data support that inhibition of PTPRS function in mDA neurons in adult mice in vivo could inhibit METH induced plasticity and behavioral sensitization.http://www.sciencedirect.com/science/article/pii/S0969996125002396PTPRSDopaminergic neuronsSynapsesParkinson's disease |
| spellingShingle | Joshua Peter Kaejaren C.N. Caldwell Lucas McClain Jason Tchieu Ashley E. Ross Yu Luo Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway Neurobiology of Disease PTPRS Dopaminergic neurons Synapses Parkinson's disease |
| title | Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway |
| title_full | Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway |
| title_fullStr | Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway |
| title_full_unstemmed | Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway |
| title_short | Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway |
| title_sort | inhibition of ptprs function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway |
| topic | PTPRS Dopaminergic neurons Synapses Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002396 |
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