Axonal Degeneration in Motor Neuron Disease

Abstract

Growing evidence from animal models and patients with amyotrophic lateral sclerosis (ALS) suggests that distal axonal degeneration begins very early in this disease, long before symptom onset and motor neuron death. The cause of axonal degeneration is unknown, and may involve local axonal damage, withdrawal of trophic support from a diseased cell body, or both. It is increasingly clear that axons are not passive extensions of their parent cell bodies, and may die by mechanisms independent of cell death. This is supported by studies in which protection of motor neurons in models of ALS did not significantly improve symptoms or prolong lifespan, likely due to a failure to protect axons. Here, we will review the evidence for early axonal degeneration in ALS, and discuss possible mechanisms by which it might occur, with a focus on oxidative stress. We contend that axonal degeneration may be a primary feature in the pathogenesis of motor neuron disease, and that preventing axonal degeneration represents an important therapeutic target that deserves increased attention.

Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS

“…Although this observation is consistent with in vivo observations that axonal degeneration appears to be an early defect that precedes the onset of ALS symptoms and motor neuron death (Fischer and Glass, 2007;Bradley et al, 1983;Fischer et al, 2004), the stem-cell-based culture system used in this study does not allow us to distinguish between developmental and degenerative changes. This issue will be addressed in future work.…”

A rapid LC-FTMS method for the analysis of cysteine, cystine and cysteine/cystine steady-state redox potential in human plasma

“…GSH, GSSG, Cys, CySS, iodoacetic acid (IAA), [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]-IAA, acetonitrile, HPLC grade water, formic acid (98%) and ammonium bicarbonate were purchased from Sigma Chemical (St. Louis, MO). IAA was recrystallized twice in petroleum ether.…”

“…Oxidative stress has been associated with aging [1] and a number of age-related diseases such as cardiovascular disease [2], neurodegeneration [3] and cancer [4]. Extensive research has led to a number of biomarkers of oxidative stress [5] although none are in widespread clinical use.…”

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

“…Additional pathological features include neuromuscular junction (NMJ) denervation, axonal degeneration, and abortive collateral sprouting (10,11). The combination of progressive motor neuron cell death and the retraction of axons from NMJs together with an impaired ability of surviving intact axons to generate compensatory axonal collateral sprouts results in progressive irreversible muscle atrophy (2,12,13).…”