Oxidative Stress Suppresses Trk Signaling While Stimulating JNK-Mediated Endocytosis and Cleavage of p75NTR: A Targetable Pathway for Neuroprotection in a Parkinson's Disease Model

The p75 Neurotrophin Receptor (p75^NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75^NTR signaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous research demonstrated that proteolytic processing of p75^NTR in this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson's disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75^NTR signaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75^NTR by promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75^NTR from the cell surface. This activation of p75^NTR signaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75^NTR processing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75^NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75^NTR cleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75^NTR in response to oxidative stress, underscore a key role for p75^NTR in dopaminergic neurodegeneration, and highlight p75^NTR as a potential therapeutic target for reducing neurodegeneration in PD.