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

Figures & data

Figure 1. SOD1-G93A transgenic mouse model research categorized by article topic frequency based on a nine-category pathophysiological function ontology. For each category, the graph illustrates the absolute article count and percentage of the total SOD1-G93A articles with primary data based on word frequency searches of the title, figure captions, and within figure text. Articles are typically classified under two or three categories due to the many inherent biological and pathological inter-category relationships.

Table I. The 12 most common terms or phrases per category are presented with a description and the resultant number of articles (A) and figures (F). Note that the 12 terms provided more than 85% coverage in each category (see Test sets).

Axonal Transport	A	F	Description/Significance
retrograde, retrogradely	44	96	The movement of dynein cargoes towards the cell body
neurite, neurites	38	53	A projection from the cell body, so an axon or dendrite.
dynein	20	84	The motor protein that is responsible for carrying cargoes retrogradely
microtubule, microtubules	17	38	Neural structure or “tracks” on which dynein and kinesin travel.
vesicle	17	38	Transport unit often carried by dynein and kinesin.
anterograde, anterogradely	16	40	The movement of kinesin cargoes from soma towards neuromuscular junction
Synaptosome(s)	11	52	A type of vesicle transported in the axon
axon terminal, projection	10	13	Catch-all terms for detecting axonal transport papers.
kinesin	7	15	The motor protein that is responsible for carrying cargoes anterogradely
loa	7	28	“Legs at Odd Angles” - mutation that affects dynein “legs” (25).
neurofilament* transport	5	16	Neural structure element carried via “slow” axonal transport.
wallerian	4	9	Wallerian Degeneration is the degeneration of an axon.
Chemistry	A	F	Description/Significance
copper, Cu2+	58	236	Used by SOD1
zinc, Zn2+	53	216	Used by SOD1
metal, metals	35	92	Catch-all terms for detecting data discussing metals
luciferase	31	41	An oxidative enzyme used in assays
iron, Fe, Fe2+	17	44	Involved in Fenton reaction, which produces hydroxyl radical
HO-1, Heme oxygenase	17	40	Enzyme that catalyzes the degradation of heme, producing iron
vitamin, B12	16	48	Tried as a treatment (32).
lithium	8	46	Tried as a treatment (33).
ferritin	8	14	Controls iron in a cell
NaHCO3	5	10	Used as a buffer in various experiments, particularly those assessing metalation
Salubrinal	4	11	Used to suppress SOD1 activity (89).
VPA	4	9	Valproic acid. Tried as a treatment (34).
Energetics	A	F	Description/Significance
mitochondrial, mitochondria, mito, mitochondrion,	194	773	Produce ATP, involved in cellular respiration & calcium homeostasis.
calcium, Ca2, Ca2+, ca	100	238	Required for respiration, excitability, and muscle contraction.
Cox, complex IV	80	135	Last enzyme in the respiratory electron transport chain
ATP, ADP, ATPase	74	129	Energy units made or used in cellular respiration
cytochrome, cytochrome c	69	141	Transfers electrons from complex III – IV
phosphorylation	47	89	Process of adding a phosphate group to a protein, turning it “on” or “off”
metabolism, metabolic	43	80	General term encompassing energy harvesting
complex I	28	51	Element of the electron transport chain of mitochondrial respiration
glucose	25	45	Main “fuel” for cellular respiration
creatine	23	75	Increases the formation of ATP
succinate	23	35	Encompasses Succinate Dehydrogenase, aka complex II, role in respiration
depolarization	19	37	Measure of mitochondrial respiration
Excitability	A	F	Description/Significance
Glutamate	108	401	Excess extracellular glutamate causes neuronal degeneration
GLT1, GLT-1, EAAT2, EAAT	56	188	Glutamate transporters; decreases observed in ALS patients and G93A mice
Na, Na+	52	112	Required for action potential; ions enter cell upon activation of glutamate receptors
Excitotoxicity, excitatory,	48	137	Terms describing toxic over-excitation
AMPA	35	107	α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid- glutamate receptor mediating fast excitatory transmission
cmap, cmaps	35	53	Compound muscle action potential-summation of several action potentials over several muscle fibers in one area
riluzole	33	85	Sodium channel blocker; the only FDA-approved drug for ALS.
NMDA	27	43	N-methyl-D-aspartate- glutamate receptor mediating slow excitatory transmission
GABA	22	50	ϒ-Aminobutyric acid- chief inhibitory neurotransmitter in mammals
GluR*, GluR1, GluR2, GluR	20	60	Glutamate receptors: Down-regulation of GluR2 leads to excess Ca2 + influx
glutamine	16	34	Neurologically inactive form - precursor - of glutamate
aspartate	16	32	Stimulates NMDA receptors, but not as strongly as glutamate does
Oxidative stress	A	F	Description/Significance
H2O2, Hydrogen peroxide	69	129	Free radical. Relatively weak but can produce stronger oxidants.
oxide	47	154	Catch-all term for elements causing oxidation
ROS, reactive oxygen species	47	90	Reactive molecules containing oxygen. Source of free radicals.
GSH, glutathione	45	101	Antioxidant that prevents damage from free radicals.
nitric, nitric oxide	43	145	Also known as NO. Common type of free radical.
Peroxidase, Peroxidation	36	84	Assist in oxidative degradation; activity is enhanced in ALS mice
nNOS, NOS	34	68	Produces NO upon stimulation by inflammatory cytokines
Peroxide, peroxides	26	44	Catch-all term for any peroxide. See hydrogen peroxide.
MDA	15	20	Marker for oxidative stress
Nrf2	15	73	Involved in antioxidant and anti-inflammatory defense (6).
GSSG	14	19	Oxidized form of glutathione
DMPO	11	27	Used in spin trapping to measure the levels of free radicals.
Inflammation	A	F	Description/Significance
GFAP	245	399	Glial fibrillary acidic protein-an indicator of the progression of gliosis
astrocyte	233	579	Astroglia that support neural function; assist in scarring following neural damage
T-cells, T-cell, CD11b, CD4	181	331	Provides neuroprotection
microglia, microglial	172	406	Excess activation leads to neurodegeneration
glial cell, glia	106	247	Catch-all terms for various glial cells.
inflam*, neuroinflamm*, immune	79	285	Catch-all terms for neuroinflammatory processes.
TNF, TNF alpha, TNFalpha, TNFa, TNF a, tumor necrosis factor	66	129	Tumor necrosis factor α. Stimulates immune activation, leading to gliosis
IL, IL 6, IL 4, interleukin	56	78	Interleukins stimulate immune cell activation, leading to gliosis
macrophage, M2, M1	53	88	Regulate immune activity via production of cytokines
VEGF	44	124	Vascular endothelial growth factor. Tried as a treatment (69)
cytokine, cytokines	38	82	Catch-all terms microglial priming and immune cell activation elements
LPS	33	56	Lipopolysaccharide- activates glial cells, inducing gliosis
Apoptosis	A	F	Description/Significance
caspase	122	225	Key apoptotic signal
apoptosis, apoptotic	114	294	Programmed cell death
akt	43	81	When activated by VGEF possibly acts as an anti-apoptotic factor
Bcl 2	31	85	A protein involved in both pro and anti-apoptotic mechanisms
bax	25	43	A pro-apoptotic protein
fmk	19	27	Anti-apoptotic signaling pathway
p75NTR	17	44	p75 neurotrophin receptor promotes caspase-dependent axon degeneration
p53	17	38	Tumor-suppressing protein in apoptosis.
L-NAME	15	28	Reduces NO and reverts the pro-apoptotic factors of it
FASL	11	26	Fas ligand; induces apoptosis when bound to its receptor
MPTP	10	27	Neurotoxin that induces apoptosis
XIAP	9	15	X-linked inhibitor of apoptosis protein
Proteomics	A	F	Description/Significance
Aggregate(s), aggregation,	168	575	Aggregates of mutant, misfolded proteins are a hallmark of ALS
ubiquitin	89	165	Affects protein degradation, trans-location, and interaction
Kinase(s)	65	193	Affects protein activity, signaling; implicated in protein aggregation in ALS
protein binding	58	109	Catch-all term for binding processes of mutant SOD1 leading to aggregation.
proteasome, proteasomal	54	143	Involved in protein degradation.
disulfide	35	131	Disulfide bonds mediate the aggregation process in SOD1
oligomer*	30	40	Catch-all term for proteins
heat shock protein, hsp	30	74	Response to proteomic stress. Up-regulation extends survival.
ER Stress	27	75	Endoplasmic reticulum stress from unfolded proteins
misfolded protein, protein fold change	27	43	The fold change (misfolded proteins) leads to protein aggregates.
protein degradation	24	36	Dysfunctional degradation of misfolded proteins causes aggregates
TDP-43, TDP 43	23	59	TAR-DNA binding protein 43. Inclusions commonly found in ALS patients.
Systemic	A	F	Description/Significance
Density, count or activity of motor neurons (all spellings)	323	483	Includes functional measures of locomotor activity and assessment of motor neuron degeneration
rotarod, rotorod, rot*rod	217	267	Experimental device and test used to assess mouse motor function
disease progression	205	553	Catch-all term for in vivo observation of disease progression.
hindlimb, forelimb, limb,	173	318	Hindlimb tremors are commonly used as a marker of disease onset
body weight	171	233	Indicator of disease progression; decreases in later stages of the disease.
lifespan, life span	121	240	The total time spent alive for the subject.
cumulative survival	103	119	The endpoint of the disease. Total lifespan of subject.
probability of onset	102	109	The time when symptoms of ALS typically begin to appear.
grip, grip strength	94	134	Test assessing mouse's ability to grip; indicator of motor function/progression
in vivo, invivo	88	209	“Within the living” - encompasses all experiments performed on live test subjects.
gastrocnemius	75	151	Large muscle found in the hindlimb, easy to access and evaluate.
fall	59	73	The action of falling down, usually due to inability to stand.

Figure 2. Field map of the most prevalent SOD1-G93A transgenic mouse research topics. The sizes of the boxes represent the relative term frequency. The map illustrates categorical terms required to encompass at least 85% of the articles classified to each of the nine categories: Apoptosis, Axonal transport, Chemistry, Energetics, Excitability, Inflammation, Oxidative stress, Proteomics, and Systemic.

Figure 3. Field map of the inflammation categories based on their pathophysiological properties and significance to demonstrate the variety of terms that were searched. The frequency search reveals that a few measures are used for specific cell types, e.g. GFAP expression was much more heavily used (by 259 articles) compared to ApoE (six articles).

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