State of the field: An informatics-based systematic review of the SOD1-G93A amyotrophic lateral sclerosis transgenic mouse model

Abstract

Numerous sub-cellular through system-level disturbances have been identified in over 1300 articles examining the superoxide dismutase-1 guanine 93 to alanine (SOD1-G93A) transgenic mouse amyotrophic lateral sclerosis (ALS) pathophysiology. Manual assessment of such a broad literature base is daunting. We performed a comprehensive informatics-based systematic review or ‘field analysis’ to agnostically compute and map the current state of the field. Text mining of recaptured articles was used to quantify published data topic breadth and frequency. We constructed a nine-category pathophysiological function-based ontology to systematically organize and quantify the field’s primary data. Results demonstrated that the distribution of primary research belonging to each category is: systemic measures an motor function, 59%; inflammation, 46%; cellular energetics, 37%; proteomics, 31%; neural excitability, 22%; apoptosis, 20%; oxidative stress, 18%; aberrant cellular chemistry, 14%; axonal transport, 10%. We constructed a SOD1-G93A field map that visually illustrates and categorizes the 85% most frequently assessed sub-topics. Finally, we present the literature-cited significance of frequently published terms and uncover thinly investigated areas. In conclusion, most articles individually examine at least two categories, which is indicative of the numerous underlying pathophysiological interrelationships. An essential future path is examination of cross-category pathophysiological interrelationships and their co-correspondence to homeostatic regulation and disease progression.

Seeking homeostasis: temporal trends in respiration, oxidation, and calcium in SOD1 G93A Amyotrophic Lateral Sclerosis mice

“…Articles were either downloaded using PubMed Central or from e-journal subscriptions available from the libraries of Georgia Institute of Technology and Emory University. Data was recaptured from the following article locations ( Kim et al, 2015 ), referred to as entities: article title; abstract; figure captions; within figure text ( x – y axis labels, bar graph categorical labels, legends, etc. ); and data series and response values (e.g., quantifiable figure/table data).…”

“…Transgenic mice, and namely the superoxide dismutase 1 glycine 93 to alanine mutation (SOD1 G93A), have served as the predominant means by which to investigate the underlying cellular pathophysiology ( Pfohl et al, 2015 ). A multitude of categorical disturbances have been identified, which are described in detail in a recent informatics-based systematic review of the SOD1 G93A field ( Kim et al, 2015 ): apoptosis, including changes in pro- and anti-apoptotic signals; energetics, including mitochondrial dysfunction, adenosine triphosphate (ATP) depletion, and calcium homeostasis; excitability, including hypoexcitability, hyperexcitability, and excitotoxicity; genetic transcription, including damage to mRNA and DNA; inflammation, due to reactive microglia and astrocytes; oxidative stress, from the production of free radicals; proteomics, including the build-up of mutant protein aggregates and reduced autophagy or proteasome function; and systemic function, which also includes potential non-neuromuscular contributors.…”

Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression

“…Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the rapid degradation of motor neurons over the course of the disease, resulting in paralysis, respiratory failure, and ultimately death. ALS is multi-faceted pathophysiology, which includes axonal transport deficiency; upregulation of apoptotic cascades; changes in cellular chemistry, including metallation and enzymes; cellular energetics deficiencies; excitability, including changes in neurotransmitters and transporters; inflammation, including increased microglia activation and gliosis; oxidative stress, including increases in free intracellular oxidants and anti-oxidants; protein deregulation, including increased protein aggregates and decreased autophagy; and systemic contributors, including those of muscular and non-neuromuscular origin (Irvin et al, 2015 ; Kim et al, 2015 ). For a recent in-depth informatics-based review of the entire SOD1 G93A field, including an overview of the nine previously mentioned pathophysiological categories, please see (Kim et al, 2015 ).…”

Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

“…We believe that the small, yet physiologically relevant, distortion of sensory populations is associated with aberrant mutant GlyRS-Trk receptor binding during development. To see whether it extends to other mouse models of neuromuscular disease, we analysed L1-L5 DRG from SOD1 G93A mice, an established model of amyotrophic lateral sclerosis (ALS), which displays a plethora of defects and dysfunctional pathways in peripheral, but mainly motor, nerves (Kim et al, 2015;Nardo et al, 2016). Lumbar DRG were dissected and immunohistochemically processed from SOD1 G93A and littermate control males at P30-31 ( Figure 3A) and P100-101 ( Figure 3C), representing pre-symptomatic and late disease stages, respectively.…”