Abstract
Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder (Brown and Al-Chalabi, 2017)
This section classifies the pathomechanisms of axonal dysfunction into six subsections, including neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching (Figure 1)
Decreased endoplasmic reticulum (ER)-mitochondria association can occur as a result of loss-of-function mutations in SIGMAR1, leading to impaired retrograde transport and, to axonal degeneration and motor neurons (MNs) death (BernardMarissal et al, 2015; Watanabe et al, 2016)
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder (Brown and Al-Chalabi, 2017). The global pathomechanisms of axons in ALS are considered in an overview of the current knowledge of axonal events in MNs. This section classifies the pathomechanisms of axonal dysfunction into six subsections, including neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching (Figure 1). Primary motor neurons expressing mutant PFN1 display smaller Destabilization of microtubules, general transport defect Molecular tether between lysosomes and RNA granules in axon Reduced kinesin-1 mediated transport, impaired neurofilament transport Altered axonal transport and vesicle trafficking, impaired signaling endosome trafficking. Decreased ER-mitochondria association can occur as a result of loss-of-function mutations in SIGMAR1, leading to impaired retrograde transport and, to axonal degeneration and MN death (BernardMarissal et al, 2015; Watanabe et al, 2016). Boyden chamber ultrasensitive sample embryos preparation technology termed single-pot solid-phase-enhanced sample preparation (SP3)
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