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The Molecular Pathway of p75 Neurotrophin Receptor (p75NTR) in Parkinson’s Disease: The Way of New Inroads

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Abstract

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease of the brain. PD is characterized by motor and non-motor symptoms. The p75 neurotrophin receptor (p75NTR) is a functional receptor for different growth factors including pro-brain derived neurotrophic factor (pro-BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Consequently, this review aimed to illustrate the detrimental and beneficial role of p75NTR in PD. Diverse studies showed that p75NTR and its downstream signaling are intricate in the pathogenesis of PD. Nevertheless, pro-apoptotic and pro-survival pathways mediated by p75NTR in PD were not fully clarified. Of note, p75NTR plays a critical role in the regulation of dopaminergic neuronal survival and apoptosis in the CNS. Particularly, p75NTR can induce selective apoptosis of dopaminergic neurons and progression of PD. In addition, p75NTR signaling inhibits the expression of transcription factors which are essential for the survival of dopaminergic neurons. Also, p75NTR expression is connected with the severity of dopaminergic neuronal injury. These verdicts implicate p75NTR signaling in the pathogenesis of PD, though the underlying mechanistic pathways remain not elucidated. Collectively, the p75NTR signaling pathway induces a double-sword effect either detrimental or beneficial depending on the ligands and status of PD neuropathology. Therefore, p75NTR signaling seems to be protective via phosphoinositide 3-kinase (PI3K)/AKT and Bcl-2 and harmful via activation of JNK, caspase 3, nuclear factor kappa B (NF-κB), and RhoA pathways.

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Author notes

  1. Naif H. Ali and Hayder M. Al-kuraishy contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Medical College, Najran University, Najran, Kingdom of Saudi Arabia

    Naif H. Ali

  2. Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq

    Hayder M. Al-kuraishy & Ali I. Al-Gareeb

  3. Clinical Neurosciences Department, College of Medicine, King Faisal University, Hofuf, Saudi Arabia

    Saud A. Alnaaim

  4. Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, 51744, Matrouh, Egypt

    Hebatallah M. Saad

  5. Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt

    Gaber El-Saber Batiha

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  1. Naif H. Ali
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Contributions

NHA, HMA-K, and AIA conceptualized the manuscript, wrote, edited, and reviewed the main text, and approved the final edition of the manuscript. SAA, HMS, and GE-SB prepared the figures, wrote, corrected, amended, and approved the final edition of the manuscript.

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Correspondence to Hebatallah M. Saad.

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Ali, N.H., Al-kuraishy, H.M., Al-Gareeb, A.I. et al. The Molecular Pathway of p75 Neurotrophin Receptor (p75NTR) in Parkinson’s Disease: The Way of New Inroads. Mol Neurobiol 61, 2469–2480 (2024). https://doi.org/10.1007/s12035-023-03727-8

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