New Insights on the Mechanisms of Disease Course Variability in ALS from Mutant SOD1 Mouse Models

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disease in terms of progression rate and survival. This is probably one of the reasons for the failure of many clinical trials and the lack of effective therapies. Similar variability is also seen in SOD1(G93A) mouse models based on their genetic background. For example, when the SOD1(G93A) transgene is expressed in C57BL6 background the phenotype is mild with slower disease progression than in the 129Sv mice expressing the same amount of transgene but showing faster progression and shorter lifespan. This review summarizes and discusses data obtained from the analysis of these two mouse models under different aspects such as the motor phenotype, neuropathological alterations in the central nervous system (CNS) and peripheral nervous system (PNS) and the motor neuron autonomous and non-cell autonomous mechanisms with the aim of finding elements to explain the different rates of disease progression. We also discuss the identification of promising prognostic biomarkers by comparative analysis of the two ALS mouse models. This analysis might possibly suggest new strategies for effective therapeutic intervention in ALS to slow significantly or even block the course of the disease.

Toward in vivo determination of peripheral nervous system immune activity in amyotrophic lateral sclerosis

“…Most human SOD1 mutation carriers likewise had the inflammatory PNS pattern that is found in SOD1 mice. Peripheral nervous system inflammation is found predominantly in the mutant SOD1 mice strain C57‐SOD1(G93A), which reveals a more benign disease course including a delayed onset of symptoms, slow disease progression, and prolonged survival . For humans, there are virtually no data on the significance of PNS inflammation in ALS, with the exception of 1 report of lower hazard of death in participants with, compared to those without, sural nerve inflammation .…”

Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis

“…A mutant SOD1 G93A mouse model of ALS on a 129Sv genetic background has an earlier age of onset than a SOD1 G93A mouse model on a C57BL6 genetic background despite an equal expression of the mutant protein (Marino et al, 2015). These mice have also faster disease progression and an intrinsic marked down-regulation of specific pathways involved in mitochondrial function and protein quality control (Nardo et al, 2013(Nardo et al, , 2016Marino et al, 2015). Conversely, ApoE2 polymorphism and lower EPHA4 expression have been correlated with delayed age of onset in ALS patients (Li et al, 2004;Van Hoecke et al, 2012).…”

Voltage-Gated Potassium Channel Antibodies in Slow-Progression Motor Neuron Disease

“…Recently, it has been demonstrated that axonal degeneration rather than motor neuron loss is the cause of disease acceleration and that the immune system made a major contribution to the variability of the disease course. In particular, the upregulation of immune molecules such as complement and MHC class I molecules may be responsible for more efficient axonal preservation in transgenic mice with slowly progressing MND [9]. …”

“…Progression of the disease is inherently heterogeneous and influenced by clinical, demographic, and genetic traits [8]. In animal models the activation of the immune response has been found to have a protective role [9]. …”