The role of reticulons in neurodegenerative diseases

Reticulons (RTNs) are a group of membrane-associated proteins mainly responsible for shaping the tubular endoplasmic reticulum network, membrane trafficking, inhibition of axonal growth, and apoptosis. These proteins share a common sequence feature, the reticulon homology domain, which consists of paired hydrophobic stretches that are believed to induce membrane curvature by acting as a wedge in bilayer membranes. RTNs are ubiquitously expressed in all tissues, but each RTN member exhibits a unique expression pattern that prefers certain tissues or even cell types. Recently, accumulated evidence has suggested additional and unexpected roles for RTNs, including those on DNA binding, autophagy, and several inflammatory-related functions. These manifold actions of RTNs account for their ever-growing recognition of their involvement in neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as hereditary spastic paraplegia. This review summarizes the latest discoveries on RTNs in human pathophysiology, and the engagement of these in neurodegeneration, along with the implications of these findings for a better understanding of the molecular events triggered by RTNs and their potential exploitation as next-generation therapeutics

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

Neurotrophins and their respective tropomyosin related kinase (Trk) receptors (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75(NTR)) play a fundamental role in the development and maintenance of the nervous system making them important targets for treatment of neurodegenerative diseases. Whereas Trk receptors are directly activated by specific neurotrophins, the p75(NTR) is a multifunctional receptor that exerts its effects via heterodimeric interactions with TrkA, TrkB, TrkC, sortilin or the Nogo receptor to regulate a wide array of cellular functions. By partnering with different receptors the p75(NTR) regulates binding of mature versus pro-neurotrophins and activation of different signaling pathways with outcomes ranging from growth and survival to cell death. While the developmental downregulation of the p75(NTR) has raised questions regarding its role in the mature nervous system, recent data have revealed widespread expression of low levels, a role in synaptic plasticity and adult neurogenesis and upregulation in response to injury or disease. Studies are needed to better understand these processes, particularly in the damaged nervous system, but will be complicated by expression of p75(NTR) on immune cells including macrophages and microglia that are intimately involved in disease and repair processes. Recent approaches that regulate p75(NTR) function with small non-peptide ligands have demonstrated potent neuroprotection in models of injury and neurodegenerative diseases that highlight the importance of the p75(NTR) as a therapeutic target. Future studies hold the promise of revealing a wealth of information on the multifaceted actions of the p75(NTR) that will inform the design of new neurotrophin-based therapies