Characterization of early pathogenesis in the SOD1^G93A mouse model of ALS: part II, results and discussion

Abstract

Pathological events are well characterized in amyotrophic lateral sclerosis (ALS) mouse models, but review of the literature fails to identify a specific initiating event that precipitates disease pathology. There is now growing consensus in the field that axon and synapses are first cellular sites of degeneration, but controversy exists over whether axon and synapse loss is initiated autonomously at those sites or by pathology in the cell body, in nonneuronal cells or even in nonmotoneurons (MNs). Previous studies have identified pathological events in the mutant superoxide dismutase 1 (SOD1) models involving spinal cord, peripheral axons, neuromuscular junctions (NMJs), or muscle; however, few studies have systematically examined pathogenesis at multiple sites in the same study. We have performed ultrastructural examination of both central and peripheral components of the neuromuscular system in the SOD1G93A mouse model of ALS. Twenty percent of MNs undergo degeneration by P60, but NMJ innervation in fast fatigable muscles is reduced by 40% by P30. Gait alterations and muscle weakness were also found at P30. There was no change in axonal transport prior to initial NMJ denervation. Mitochondrial morphological changes are observed at P7 and become more prominent with disease progression. At P30 there was a significant decrease in excitatory axo-dendritic and axo-somatic synapses with an increase in C-type axo-somatic synapses. Our study examined early pathology in both peripheral and central neuromuscular system. The muscle denervation is associated with functional motor deficits and begins during the first postnatal month in SOD1G93A mice. Physiological dysfunction and pathology in the mitochondria of synapses and MN soma and dendrites occur, and disease onset in these animals begins more than 2 months earlier than originally thought. This information may be valuable for designing preclinical trials that are more likely to impact disease onset and progression.

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

“…It remains an open question to what extent symptoms of ALS are preceded by temporally remote cellular abnormalities [Eisen et al, 2014]. Although animal models of ALS demonstrate abnormal neural architecture and function during embryonic stages [Martin et al, 2013; Vinsant et al, 2013], human epidemiological [Byrne et al, 2013; Schoder et al, 2010] and pathological [Proudfoot et al, 2014a] links to neurodevelopmental disorders remain sparse. Suggestions that ALS (or FTD) pathology might manifest in a behavioural prodrome long before diagnostic symptoms remain speculative [Eisen et al, 2014; Lule et al, 2008].…”

The identification of a novel isoform of EphA4 and ITS expression in SOD1 G93A mice

“…The SOD1 G93A mouse model of ALS was used to investigate the involvement of full-length EphA4 (EphA4-FL) and its alternative transcripts in ALS (Gurney et al, 1994). Based on the pathogenesis in SOD1 G93A mice (Vinsant et al, 2013), the presymptomatic stage was defined as postnatal day (P) 35. SOD1 G93A mice were immediately euthanised if they showed any of the following signs (also defined as the survival end-point): loss of the righting reflex (unable to right within 30 seconds of being placed on their back), excessive weight loss (greater than 20% of the highest body weight), or complete paralysis of any hind-limb that rendered the animal incapable of reaching food and water (Weydt et al, 2003).…”

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

“…The most commonly used transgenic mouse model is the SOD1-G34A line. These transgenic mice express mutant forms of the human SOD1 gene and multiple copies of the wild type (wt) human SOD1 gene, therefore, providing the opportunity to study the progression of ALS pathogenesis [76,77]. Recent studies suggest that the above mentioned histopathological and biochemical hallmarks result from impaired energy metabolism.…”