Phenotypes Associated with This Genotype

Genotype
MGI:3688004

• Allelic Composition: Tg(SOD1*G93A)1Gur/0
• Genetic Background: involves: C57BL/6 * SJL

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

Presence of neurofilament spheroids in the spinal cord of an 82-day old Tg(SOD1)2Gur/0 mouse

mortality/aging

premature death ( J:84843 , J:109423 , J:109458 , J:115355 , J:130581 )

• die after 124 4 days (J:84843)

• die within 7-10 days after paralysis (J:109423)

• Background Sensitivity: increased survival on C57BL/6J background (50% survival at 157.1+/-9.3 days) in contrast to B6SJL background (50% survival at 128.9+/-9.1 days) (J:115355)

growth/size/body

decreased body weight ( J:91800 )

• lower body mass

weight loss ( J:130581 )

• body weight begins to significantly decrease at 77 days of age

nervous system

gliosis ( J:55026 , J:130581 )

• resting microglial cells in the white matter of the spinal cord (J:55026)

• reactive microglial cells in the gray matter of the spinal cord at 117 and165 days of age (J:55026)

• using MAC-1 and F4/80 as specific markers of microglial cells (J:55026)

• gliosis and microglial activation are seen in the spinal cord by 90 days of age (J:130581)

astrocytosis ( J:55026 , J:76718 )

• resting astrocytes in the white matter of the spinal cord at both the cervical and lumbar levels (J:55026)

• reactive astrocytes in the gray matter of the spinal cord at 117 and165 days of age, predominated in the anterior horn of the spinal cord (J:55026)

• using GFAP as a specific marker of astrocytes (J:55026)

• exhibit astrocytosis in spinal cord, mainly in the anterior and lateral horns (J:76718)

abnormal spinal cord morphology ( J:76718 )

• exhibit neurofilament-rich spheroids at 82-days of age, similar to those seen in human amyotrophic lateral sclerosis; other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulate in the spheroids

• more spheroids are seen in cervical and thoracic regions compared to lumbar and sacral spinal cord in early symptomatic mutants, however similar numbers at all spinal cord levels are seen in older mutants

• spheroids are more frequently found in the anterior horn and in the anterior and lateral columns of the white matter than in the posterior horn

• exhibit thickened dystrophic neurites filled with immunoreactive neurofilament-rich inclusions

abnormal motor neuron morphology ( J:111890 )

• mutant SOD1-positive inclusions in the ventral horn starting at P30

• the number of motoneurons with aggregates decreased dramatically over time

decreased motor neuron number ( J:84843 )

• motoneuron loss beyond 3 months of age

motor neuron degeneration ( J:76718 , J:130581 )

• develop motor neuron disease; exhibit degenerating motor neurons filled with perikaryal vacuoles in the anterior and lateral horns (J:76718)

• significant decrease in sciatic motor neuron survival by 90 days of age (J:130581)

abnormal nervous system physiology ( J:109458 )

• mutants develop amyotrophic lateral sclerosis-like disease, with onset of disease on average at 103.2 days

increased cerebral infarct size ( J:61249 )

• increased infarct volume at 24 hours after transient focal cerebral ischemia

abnormal neuron physiology ( J:130581 )

• increased expression of unfolded protein response target genes by 50 days of age in motor neurons

impaired synaptic plasticity ( J:109423 )

• abnormal corticostriatal synaptic plasticity between postnatal days 100 and 110

abnormal CNS synaptic transmission ( J:109423 )

abnormal excitatory postsynaptic potential ( J:109423 )

• intracellular recordings of single excitatory postsynaptic potentials from striatal medium spiny neurons showing an LTP, instead of an LTD

abnormal long-term potentiation ( J:109423 )

• a tetanic stimulation induced a long term potential (LTP), instead of an long term depression (LTD) in field potentials induced in the striatum following corticostriatal pathway stimulation

reduced long-term depression ( J:109423 )

• in the presence of the N-methyl-D-aspartic acid (NMDA) receptor antagonist AP5, repetitive stimulation of the corticostriatal pathway results in LTD

• the degree of field-amplitude depression is smaller in the presence of the NMDA receptor antagonist AP5

• exogenous dopamine (DA) restores LTD

• the presence of the selective DA D2 receptor agonist restores LTD

abnormal paired-pulse inhibition ( J:109423 )

• trend towards less susceptible to paired-pulse depression

behavior/neurological

abnormal active avoidance behavior ( J:109423 )

• less conditioned responses

• less increased performance as training proceeds

• normal minimal foot-shock intensity eliciting vocalization

abnormal motor capabilities/coordination/movement ( J:76718 )

• the first signs of motor neuron disease, hyperflexia, crossed spread of spinal reflexes, and shaking of the limbs when suspended in the air, occur by 91 days of age

impaired coordination ( J:84843 )

• unable to stay for 2 min on the rotarod beyond 118 4 days of age

decreased grip strength ( J:130581 )

• steady decline in paw grip endurance beginning at 77 days of age

abnormal locomotor behavior ( J:109423 )

• locomotor activity decreases more rapidly across 5 sessions

abnormal gait ( J:130581 )

• impairment in walking patterns with reduced stride length beginning at 90 days of age

short stride length ( J:130581 )

• beginning at 90 days of age

paralysis ( J:76718 , J:109423 )

• end-stage disease occurs at an average of 136 days, with mutants exhibiting severe paralysis and inability to forge for food or water (J:76718)

• develop paralysis rapidly after signs of hindlimb weakness (J:109423)

hindlimb paralysis ( J:76718 )

• develop a progressive worsening paresis involving primarily the hind limbs with atrophy of the skeletal musculature

muscle

skeletal muscle atrophy ( J:76718 )

• develop atrophy of skeletal musculature

abnormal muscle physiology ( J:111498 )

• mice exhibit decreased muscle tetanic force compared with wild-type mice

• mice exhibit reduced survival of motor units compared with wild-type mice

• the extensor digitorum longus exhibits fatigue resistance compared with wild-type muscles

muscle weakness ( J:84843 , J:109423 )

• severe muscle weakness beyond 3 months of age (J:84843)

• hindlimb weakness from 4 months of age (J:109423)

adipose tissue

abnormal adipose tissue morphology ( J:91800 )

• exhibit reduced adipose tissue accumulation

abnormal fat pad morphology ( J:91800 )

• epididymal and retroperitoneal white adipose tissue is markedly reduced or almost nonexistent in the asymptomatic phase of the disease

homeostasis/metabolism

abnormal circulating hormone level ( J:91800 )

increased circulating corticosterone level ( J:91800 )

decreased circulating insulin level ( J:91800 )

decreased circulating leptin level ( J:91800 )

• plasma leptin levels are diminished

abnormal energy expenditure ( J:91800 )

• exhibit increased energy expenditure at rest

abnormal nitric oxide homeostasis ( J:55026 )

• increased spinal cord iNOS activity at 117 and 165 days of age

• decreased spinal cord nNOS activity at 165 days of age

increased oxygen consumption ( J:91800 )

• exhibit higher rates of total oxygen consumption

increased cerebral infarct size ( J:61249 )

• increased infarct volume at 24 hours after transient focal cerebral ischemia

cellular

abnormal cell physiology ( J:61249 )

• decreased glutamate uptake in synaptosomes

increased cellular sensitivity to oxidative stress ( J:61249 )

• increased basal and induced lipid peroxidation levels in synaptosomes

decreased cellular glucose uptake ( J:61249 )

• decreased glucose uptake in synaptosomes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
amyotrophic lateral sclerosis type 1		DOID:0060193	OMIM:105400	J:76718 , J:91800 , J:109458 , J:130581