LM11a-31 Inhibits p75 Neurotrophin Receptor (p75^NTR) Cleavage and is Neuroprotective in a Cell Culture Model of Parkinson’s Disease

Abstract

The p75 Neurotrophin Receptor (p75NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75NTRsignaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous work demonstrated that proteolytic processing of p75NTRin 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 p75NTRsignaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75NTRby promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75NTRfrom the cell surface. This activation of p75NTRsignaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75NTRprocessing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75NTRcleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75NTRin response to oxidative stress, underscore a key role for p75NTRin dopaminergic neurodegeneration, and highlight p75NTRas a potential therapeutic target for reducing neurodegeneration in PD.