Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motoneurons and degradation of the neuromuscular junctions (NMJ). Consistent with the dying-back hypothesis of motoneuron degeneration the decline in synaptic function initiates from the presynaptic terminals in ALS. Oxidative stress is a major contributory factor to ALS pathology and affects the presynaptic transmitter releasing machinery. Indeed, in ALS mouse models nerve terminals are sensitive to reactive oxygen species (ROS) suggesting that oxidative stress, along with compromised mitochondria and increased intracellular Ca2+ amplifies the presynaptic decline in NMJ. This initial dysfunction is followed by a neurodegeneration induced by inflammatory agents and loss of trophic support. To develop effective therapeutic approaches against ALS, it is important to identify the mechanisms underlying the initial pathological events. Given the role of oxidative stress in ALS, targeted antioxidant treatments could be a promising therapeutic approach. However, the complex nature of ALS and failure of monotherapies suggest that an antioxidant therapy should be accompanied by anti-inflammatory interventions to enhance the restoration of the redox balance.
Highlights
Reviewed by: David Marcinek, University of Washington, USA Dan Lindholm, Helsinki university, Finland Andreas H
neuromuscular junctions (NMJ) AS A VULNERABLE TARGET OF Amyotrophic lateral sclerosis (ALS) (DYING BACK HYPOTHESIS) Temporal analysis of axon and neuromuscular junction (NMJ) degeneration in sporadic ALS and mouse mutant SOD1 cases indicate that motoneuron pathology begins distally from the synaptic area (Figure 1) markedly earlier than clinical symptoms and proceeds towards soma in a retrograde dying back manner (Fischer et al, 2004; Rocha et al, 2013)
The motor nerve terminals are covered by the Terminal Schwann Cells (TSC) which can contribute to ALS progression
Summary
Reviewed by: David Marcinek, University of Washington, USA Dan Lindholm, Helsinki university, Finland Andreas H. Consistent with the dying-back hypothesis of motoneuron degeneration the decline in synaptic function initiates from the presynaptic terminals in ALS.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have