The proNGF-p75NTR-Sortilin Signalling Complex as New Target for the Therapeutic Treatment of Parkinsons Disease

Abstract

Growing evidence has shown that the p75 neurotrophin receptor (p75NTR) may play important roles in controlling neuronal survival or cell apoptosis within the central nervous system in development, and in pathological or neural injury. Recent studies have further revealed that p75NTR acts as a "molecular signal switch" that determines cell death or survival by three processes. First, pro-nerve growth factor (proNGF) triggers cell apoptosis by its high affinity binding to p75NTR, while NGF induces neuronal survival with low-affinity binding. Second, p75NTR mediates cell death by combining with co-receptor sortilin, whereas it promotes neuronal survival through combination with proNGF. Third, release of the intracellular domain chopper or cleavaged "short p75NTR" can independently initiate neuronal apoptosis. We have identified the cell self-destructive proNGF-p75NTR-sortilin signalling apparatus assembled in ventral tier dopamine neurons of the substantia nigra pars compacta, suggesting that p75NTR signalling might be involved in selective cell death mechanisms of substantia nigra neurons or disease progression of Parkinson's disease (PD). In addition, experimental manipulation of p75NTR benefited cell survival of cholinergic or motor neurons and improved disease progression of the neurodegenerative diseases Alzheimer's disease and Amyotrophic lateral sclerosis. The proNGF-p75NTR-sortilin signalling complex may thus provide new target for neuroprotection of substantia nigra neurons and the therapeutic treatment of PD.

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

“…Increases in proNGF in AD and Parkinson disease(Fahnestock et al, 2001; Peng et al, 2004; Pedraza et al, 2005; Chen et al, 2008) indicate that the environment is favorable for p75 NTR signaling and supports the theory that age-related damage is due to a shift toward proNGF/p75 NTR signaling versus beneficial NGF/TrkA signaling.…”

“…More recently, efforts have been directed to the potential use of non-peptide drugs that directly influence neurotrophin receptor function(Longo and Massa, 2013) or have indirect effects on neurotrophin signaling via transactivation or induction of neurotrophin secretion(Tanis et al, 2007; Obianyo and Ye, 2013; Steiner and Nath, 2014). The potential role of the p75 NTR as a therapeutic target for the treatment of neurodegenerative diseases has been recognized in recent reviews(Chen et al, 2008; Ibanez and Simi, 2012; Longo and Massa, 2013). …”

The TrkB-Positive Dopaminergic Neurons are Less Sensitive to MPTP Insult in the Substantia Nigra of Adult C57/BL Mice

“…In addition, up-regulation of p75 neurotrophic factor receptor and sortilin, which can mediate cell apoptosis, was detected in the substantia nigra in the early stage of kainic acid and MPTP mouse model [47, plus personal unpublished data]. The interactions of p75, Trks and sortilin signaling might exist in the substantia nigra of various injury events, in which neurotrophin-triggered p75-Trk receptor signaling promoted neuronal survival or regeneration, while pro-neurotrophin-triggered p75-sortilin signaling induced neuronal apoptosis or degeneration [8]. Blocking of proneurotrophin-p75-sortilin degenerative signaling and up-regulating of neurotrophin-p75-Trk signaling should be taken into account in neuroprotection strategies, and new therapeutic manipulations will be hopefully developed by targeting on BDNF-TrkB signaling in protection treatment of PD in human beings [24,50].…”

Sortilin Participates in Light-dependent Photoreceptor Degeneration in Vivo

“…In fact, the expression of both p75 NTR and sortilin is increased after neuronal stress situations such as facial nerve injury [16] or retrovirus-induced spongiform encephalomyelopathy [17]. Moreover, the proNGF/sortilin/p75 NTR complex has been shown to participate in neurodegenerative processes, including Parkinson's disease [18] and age-related neurodegeneration [14], [19], [20].…”