behavior/neurological phenotype

• hypoactivity
  • mice exhibit decreased locomotor activity compared to wild-type mice after day 115
  (MGI Ref ID J:107901)

growth/size/body region phenotype

• decreased body weight
  • body weights are lower than in wild-type mice and continues to deteriorate after day 115
  (MGI Ref ID J:107901)

mortality/aging

• premature death
  • mice reach end stage by day 147 +/-2.5 SEM (standard error of measurement)
  (MGI Ref ID J:107901)

nervous system phenotype

• abnormal spinal cord morphology
  • degeneration of the motor neurons in the cervical and lumbar spinal cord is visible at end stage with astrocytosis and vacuolization
  (MGI Ref ID J:107901)

• decreased motor neuron number
  • 50% of motor neurons in the cervical spinal cord and 60% in lumbar spinal cord are degenerated at day 152
  (MGI Ref ID J:107901)

• astrocytosis
  • astrocytosis is evident in the spinal cord
  (MGI Ref ID J:107901)

mortality/aging

• premature death
  • mice reach end stage by day 131.1¿3.7
  (MGI Ref ID J:105092)

nervous system phenotype

• decreased sensory neuron number
  • lose 53% of total dorsal root axons by day 80
  (MGI Ref ID J:105092)

behavior/neurological phenotype

• abnormal fear-related response
  • a stronger amount of freezing and run a shorter distance in comparison with wild-type following the three tone alone presentations on day 3
  (MGI Ref ID J:149044)
  • impaired extinction of conditioned fear
  (MGI Ref ID J:149044)

cellular phenotype

• abnormal mitochondrial morphology
  • vacuoles in large swollen mitochondria in the cell bodies and proximal dendrites of some motoneurons and in dendrites within in the neuropil at 10 weeks of age
  (MGI Ref ID J:144199)
  • fulminant mitochondrial swelling at 12 weeks of age
  (MGI Ref ID J:144199)

nervous system phenotype

• abnormal dendritic spine morphology
  • decreased spine density on basal dendrite segments of branch order four
  (MGI Ref ID J:149044)

• abnormal motor neuron morphology
  • swollen, degenerating axons with segmental enlargements in the ventral horn neuropil and white matter starting at 10 weeks of age
  (MGI Ref ID J:144199)
  • decreased number of mid-size (20-30 micrometer) motoneurons at 14 weeks of age
  (MGI Ref ID J:144199)
  • the residual motoneurons tend to be smaller than that the typical alpha-motoneurons at 16 weeks of age
  (MGI Ref ID J:144199)
  • cytoplasmic vacuoles starting at 10 weeks of age
  (MGI Ref ID J:144199)
  • the average size of motoneurons gradually increases from 10 weeks of age and reaches maximum at 12 weeks
  (MGI Ref ID J:144199)

• abnormal dendrite morphology
  • reduction in dendrite length and branch nodes on basal dendrites of prelimbic/infralimbic medial prefrontal cortex neurons
  (MGI Ref ID J:149044)
  • smaller diameter of basal dendrites on branch order one
  (MGI Ref ID J:149044)

• abnormal neuron morphology
  • about 20% lower glycinergic synapses (GlyT2-boutons) densities on lumbar spinal motoneurons in asymptomatic 8-week-old mice
  (MGI Ref ID J:144199)
  • the number of GlyT2-boutons is reduced further at 12 and 14 weeks of age
  (MGI Ref ID J:144199)
  • the density of GlyT2-boutons shows a slight recovery at 10 weeks of age compared with 8-week-old transgenic mice
  (MGI Ref ID J:144199)
  • decreased number of Renshaw cells at 12 and 14 weeks of age
  (MGI Ref ID J:144199)
  • majority of GlyT2-boutons is lost at 16 weeks of age
  (MGI Ref ID J:144199)

• abnormal spinal cord interneuron morphology
  • the density of GlyT2-boutons shows a slight recovery at 10 weeks of age compared with 8-week-old transgenic mice
  (MGI Ref ID J:144199)
  • majority of GlyT2-boutons is lost at 16 weeks of age
  (MGI Ref ID J:144199)
  • the number of GlyT2-boutons is reduced further at 12 and 14 weeks of age
  (MGI Ref ID J:144199)
  • about 20% lower GlyT2-boutons densities on lumbar spinal motoneurons in asymptomatic 8-week-old mice
  (MGI Ref ID J:144199)
  • decreased density of ChAT-boutons at 16 weeks of age
  (MGI Ref ID J:144199)
  • decreased number of Renshaw cells at 12 and 14 weeks of age
  (MGI Ref ID J:144199)

• abnormal spinal cord ventral horn morphology
  • swollen, degenerating axons with segmental enlargements in the ventral horn neuropil at 10 weeks of age
  (MGI Ref ID J:144199)

• abnormal cholinergic neuron morphology
  • decreased density of ChAT-boutons at 16 weeks of age
  (MGI Ref ID J:144199)

• decreased motor neuron number
  • the number of motoneurons is reduced further at 16 weeks of age
  (MGI Ref ID J:144199)
  • decreased number of motoneurons at 14 weeks of age
  (MGI Ref ID J:144199)

• motor neuron degeneration
  • decreased number of motoneurons at 14 weeks of age
  (MGI Ref ID J:144199)
  • swollen, degenerating axons with segmental enlargements in the ventral horn neuropil at 10 weeks of age
  (MGI Ref ID J:144199)
  • the number of motoneurons is reduced further at 16 weeks of age
  (MGI Ref ID J:144199)

• abnormal spinal cord morphology
  • cytoplasmic vacuoles in some motoneuron cell bodies and proximal dendrites in lumbar spinal cord at 10 weeks of age
  (MGI Ref ID J:144199)
  • more apparent cytoplasmic vacuoles in motoneurons and more motoneurons possessed vacuoles at 12 weeks of age
  (MGI Ref ID J:144199)

• abnormal spinal cord white matter morphology
  • swollen, degenerating axons with segmental enlargements in the white matter at 10 weeks of age
  (MGI Ref ID J:144199)

cellular phenotype

• abnormal cell physiology
  • decreased glutamate uptake in synaptosomes
  (MGI Ref ID J:61249)

• increased cellular sensitivity to oxidative stress
  • increased basal and induced lipid peroxidation levels in synaptosomes
  (MGI Ref ID J:61249)

• decreased cellular glucose uptake
  • decreased glucose uptake in synaptosomes
  (MGI Ref ID J:61249)

adipose tissue phenotype

• abnormal fat pad morphology
  • epididymal and retroperitoneal white adipose tissue is markedly reduced or almost nonexistent in the asymptomatic phase of the disease
  (MGI Ref ID J:91800)

• abnormal adipose tissue morphology
  • exhibit reduced adipose tissue accumulation
  (MGI Ref ID J:91800)

growth/size/body region phenotype

• weight loss
  • body weight begins to significantly decrease at 77 days of age
  (MGI Ref ID J:130581)

• decreased body weight
  • lower body mass
  (MGI Ref ID J:91800)

homeostasis/metabolism phenotype

• abnormal circulating hormone level
  (MGI Ref ID J:91800)

• abnormal energy expenditure
  • exhibit increased energy expenditure at rest
  (MGI Ref ID J:91800)

• abnormal nitric oxide homeostasis
  • decreased spinal cord nNOS activity at 165 days of age
  (MGI Ref ID J:55026)
  • increased spinal cord iNOS activity at 117 and 165 days of age
  (MGI Ref ID J:55026)

• increased cerebral infarct size
  • increased infarct volume at 24 hours after transient focal cerebral ischemia
  (MGI Ref ID J:61249)

• decreased circulating insulin level
  (MGI Ref ID J:91800)

• decreased circulating leptin level
  • plasma leptin levels are diminished
  (MGI Ref ID J:91800)

• increased circulating corticosterone level
  (MGI Ref ID J:91800)

• increased oxygen consumption
  • exhibit higher rates of total oxygen consumption
  (MGI Ref ID J:91800)

mortality/aging

• premature death
  • die within 7-10 days after paralysis
  (MGI Ref ID 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)
  (MGI Ref ID J:115355)(MGI Ref ID J:109458)
  • die after 124 ± 4 days
  (MGI Ref ID J:84843)
  • die after 124 ¿ 4 days
  (MGI Ref ID J:84843)

muscle phenotype

• skeletal muscle atrophy
  • develop atrophy of skeletal musculature
  (MGI Ref ID J:76718)

• abnormal muscle physiology
  • the extensor digitorum longus exhibits fatigue resistance compared with wild-type muscles
  (MGI Ref ID J:111498)
  • mice exhibit decreased muscle tetanic force compared with wild-type mice
  (MGI Ref ID J:111498)
  • mice exhibit reduced survival of motor units compared with wild-type mice
  (MGI Ref ID J:111498)

• muscle weakness
  • hindlimb weakness from 4 months of age
  (MGI Ref ID J:109423)
  • severe muscle weakness beyond 3 months of age
  (MGI Ref ID J:84843)

nervous system phenotype

• abnormal CNS synaptic transmission
  (MGI Ref ID J:109423)

• abnormal spinal cord morphology
  • exhibit thickened dystrophic neurites filled with immunoreactive neurofilament-rich inclusions
  (MGI Ref ID J:76718)
  • 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
  (MGI Ref ID J:76718)
  • 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
  (MGI Ref ID 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
  (MGI Ref ID J:76718)

• astrocytosis
  • 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
  (MGI Ref ID J:55026)
  • exhibit astrocytosis in spinal cord, mainly in the anterior and lateral horns
  (MGI Ref ID J:76718)
  • resting astrocytes in the white matter of the spinal cord at both the cervical and lumbar levels
  (MGI Ref ID J:55026)
  • using GFAP as a specific marker of astrocytes
  (MGI Ref ID J:55026)

• decreased motor neuron number
  • motoneuron loss beyond 3 months of age
  (MGI Ref ID J:84843)

• abnormal motor neuron morphology
  • the number of motoneurons with aggregates decreased dramatically over time
  (MGI Ref ID J:111890)
  • mutant SOD1-positive inclusions in the ventral horn starting at P30
  (MGI Ref ID J:111890)

• gliosis
  • reactive microglial cells in the gray matter of the spinal cord at 117 and165 days of age
  (MGI Ref ID J:55026)
  • using MAC-1 and F4/80 as specific markers of microglial cells
  (MGI Ref ID J:55026)
  • gliosis and microglial activation are seen in the spinal cord by 90 days of age
  (MGI Ref ID J:130581)
  • resting microglial cells in the white matter of the spinal cord
  (MGI Ref ID J:55026)

• motor neuron degeneration
  • develop motor neuron disease; exhibit degenerating motor neurons filled with perikaryal vacuoles in the anterior and lateral horns
  (MGI Ref ID J:76718)
  • significant decrease in sciatic motor neuron survival by 90 days of age
  (MGI Ref ID J:130581)

• reduced long term depression
  • exogenous dopamine (DA) restores LTD
  (MGI Ref ID J:109423)
  • the presence of the selective DA D2 receptor agonist restores LTD
  (MGI Ref ID 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
  (MGI Ref ID J:109423)
  • the degree of field-amplitude depression is smaller in the presence of the NMDA receptor antagonist AP5
  (MGI Ref ID J:109423)

• abnormal paired-pulse inhibition
  • trend towards less susceptible to paired-pulse depression
  (MGI Ref ID J:109423)

• abnormal neuron physiology
  • increased expression of unfolded protein response target genes by 50 days of age in motor neurons
  (MGI Ref ID J:130581)

• abnormal excitatory postsynaptic potential
  • intracellular recordings of single excitatory postsynaptic potentials from striatal medium spiny neurons showing an LTP, instead of an LTD
  (MGI Ref ID J:109423)

• impaired synaptic plasticity
  • abnormal corticostriatal synaptic plasticity between postnatal days 100 and 110
  (MGI Ref ID J:109423)

• abnormal long term potentiation
  • 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
  (MGI Ref ID J:109423)

• increased cerebral infarct size
  • increased infarct volume at 24 hours after transient focal cerebral ischemia
  (MGI Ref ID J:61249)

• abnormal nervous system physiology
  • mutants develop amyotrophic lateral sclerosis-like disease, with onset of disease on average at 103.2 days
  (MGI Ref ID J:109458)

behavior/neurological phenotype

• abnormal motor capabilities/coordination/movement
  • 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
  (MGI Ref ID J:76718)

• short stride length
  • beginning at 90 days of age
  (MGI Ref ID J:130581)

• abnormal active avoidance behavior
  • less conditioned responses
  (MGI Ref ID J:109423)
  • normal minimal foot-shock intensity eliciting vocalization
  (MGI Ref ID J:109423)
  • less increased performance as training proceeds
  (MGI Ref ID J:109423)

• paralysis
  • develop paralysis rapidly after signs of hindlimb weakness
  (MGI Ref ID 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
  (MGI Ref ID J:76718)

• abnormal gait
  • impairment in walking patterns with reduced stride length beginning at 90 days of age
  (MGI Ref ID J:130581)

• decreased grip strength
  • steady decline in paw grip endurance beginning at 77 days of age
  (MGI Ref ID J:130581)

• impaired coordination
  • unable to stay for 2 min on the rotarod beyond 118 ¿ 4 days of age
  (MGI Ref ID J:84843)

• abnormal locomotor behavior
  • locomotor activity decreases more rapidly across 5 sessions
  (MGI Ref ID J:109423)

• hindlimb paralysis
  • develop a progressive worsening paresis involving primarily the hind limbs with atrophy of the skeletal musculature
  (MGI Ref ID J:76718)

muscle phenotype

• muscle weakness
  • progressive reduced forelimb and hindlimb grip force from the onset of testing (64 days of age)
  (MGI Ref ID J:130811)
  • progressive decrease in tongue force beginning at approximately 113 days of age
  (MGI Ref ID J:130811)

• progressive muscle weakness
  • after 120 days of age
  (MGI Ref ID J:103582)
  • dragging in one hindlimb and inability to grasp a cage bar at 103 days of age
  (MGI Ref ID J:146652)
  • paralysis progresses to both hindlimbs within 3-4 days
  (MGI Ref ID J:146652)

• abnormal muscle physiology
  • greater osmotic stress-induced Ca²⁺ release activity in fiber segments with depolarized mitochondria
  (MGI Ref ID J:158298)

• abnormal skeletal muscle fiber morphology
  • enlarged mitochondria with vacuoles, invading the sarcomeric A band
  (MGI Ref ID J:158298)

nervous system phenotype

• abnormal astrocyte morphology
  • characterized by mitochondrial damage, cellular edema and cell rupture
  (MGI Ref ID J:165019)
  • swollen, progressive degeneration of astrocytes in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)

• abnormal brainstem morphology
  • increased area of the brainstem nuclei (hypoglossal and facial nucleus) between 80 and 120 days after birth
  (MGI Ref ID J:127265)
  • continuous age-dependent increased number of vacuoles
  (MGI Ref ID J:127265)
  • vacuoles in the trigeminal nucleus and the locus coeruleus neuropil at 3 months of age
  (MGI Ref ID J:110437)
  • swollen neurites and vacuoles in the brainstem affecting cerebellar and various motor nuclei (the hypoglossal, the ambiguus and the facial nucleus) within the following month
  (MGI Ref ID J:110437)
  • increased number of vacuoles in the brainstem nuclei from Day 80 onwards
  (MGI Ref ID J:127265)
  • continuous age-dependent T2 values increase
  (MGI Ref ID J:127265)
  • degeneration of brainstem motor nuclei (the trigeminal, hypoglossal and facial nucleus as early as Day 80 by magnetic resonance imaging (MRI)
  (MGI Ref ID J:127265)
  • H&E staining with brain sections show same morphological alterations
  (MGI Ref ID J:127265)
  • higher relaxation parameter T2 values for all the three brainstem nuclei after 80 days
  (MGI Ref ID J:127265)

• abnormal motor neuron morphology
  • mitochondria with swollen cristae in both axons and dendrites near capillaries
  (MGI Ref ID J:165019)
  • large membrane bound vacuoles consisting of either dilated axons or dendrite
  (MGI Ref ID J:165019)
  • most ventral horn motor neurons lack autofluorescent lipofuscin in cell bodies at 3 months of age
  (MGI Ref ID J:212250)
  • paler and more strongly stained motoneurons, with vacuolation in the more strongly stained motoneurons by 6 weeks
  (MGI Ref ID J:146652)
  • decreased mitochondria in axonal mitochondria
  (MGI Ref ID J:129976)
  • Normal - however, lipofuscin is detected in the neuron cell bodies of the dorsal regions of the spinal cord gray matter
  (MGI Ref ID J:212250)
  • more electron-lucent than electron-dense motoneurons by 18 weeks, and many motoneurons exhibit extensive vacuolation
  (MGI Ref ID J:146652)
  • increased intermitochondrial distance by 30-50% in axons
  (MGI Ref ID J:129976)
  • increased mitochondria in cell bodies of motoneurons
  (MGI Ref ID J:129976)

• abnormal nervous system physiology
  • partially ameliorated by creatine administration
  (MGI Ref ID J:111280)
  • lower basal ATP levels in cerebral cortex in 30-day-old mice
  (MGI Ref ID J:111280)
  • reduced ADP levels by 60 days of age
  (MGI Ref ID J:111280)
  • the extent of impairment in ATP production progresses with age
  (MGI Ref ID J:111280)
  • reduced creatine levels by 90 days of age in both cerebral cortex and spinal cord
  (MGI Ref ID J:111280)

• abnormal oculomotor nucleus morphology
  • heavily filled with Gallyas+, coiled and ballooned axonal and dendritic profiles in the oculomotor ,the trochlear nucleus at 4 months of age
  (MGI Ref ID J:110437)

• abnormal spinal cord morphology
  • increase with disease progression, 36-fold by day 135
  (MGI Ref ID J:143173)
  • natural killer cell in spinal cords
  (MGI Ref ID J:143173)
  • restricted to the ventral horns of spinal cords at the age of 2 months
  (MGI Ref ID J:110437)
  • increase and extend into the dorsal horn of the spinal cord within the following month
  (MGI Ref ID J:110437)
  • increased lymphocyte population in spinal cords at day 65
  (MGI Ref ID J:143173)
  • significant accumulation of CD4+ and CD8+ T cells in spinal cords
  (MGI Ref ID J:143173)
  • swollen neurites and vacuoles of various dimensions and large neuritic spheroids in some spinal motor neurons at the age of 2 months
  (MGI Ref ID J:110437)

• abnormal substantia nigra morphology
  • degeneration lesions in the substantia nigra
  (MGI Ref ID J:110437)

• abnormal superior colliculus morphology
  • degeneration lesions in the deep layers of the colliculi superior
  (MGI Ref ID J:110437)

• abnormal synaptic bouton morphology
  • degenerative changes occurred in all classes of terminal at 6, 10 and 18 weeks of age, apart from the C-type terminal
  (MGI Ref ID J:146652)
  • reduction in both terminal number and coverage of the somal membrane, and decline further by around 60% at 18 weeks of age
  (MGI Ref ID J:146652)
  • increased length of the subsynaptic cistern of C-terminals
  (MGI Ref ID J:146652)
  • increase in the membrane coverage of C-terminals at 6, 10 and 18 weeks of age
  (MGI Ref ID J:146652)
  • thin glial processes either partly or totally engulfed some terminals at 18 weeks of age
  (MGI Ref ID J:146652)
  • increase in the proportional numbers of C-terminals at 6 and 18 weeks of age
  (MGI Ref ID J:146652)
  • increased number of the Nissl body rER lamellae of C-terminals at 18 weeks of age
  (MGI Ref ID J:146652)
  • increased overall length of the Nissl body rER lamellae of C-terminals at 10 and 18 weeks of age
  (MGI Ref ID J:146652)
  • increased size of the postsynaptic structure of C-terminals
  (MGI Ref ID J:146652)
  • progressive enlargement of the C-terminal presynaptic terminal at 10 and 18 weeks of age
  (MGI Ref ID J:146652)

• decreased motor neuron number
  • loss of 30% of corticospinal, 33% of bulbospinal and 33% of rubrospinal neurons at 90 days
  (MGI Ref ID J:133155)
  • small loss of corticospinal (9%), bulbospinal (12%) and rubrospinal (14%) projections at 60 days
  (MGI Ref ID J:133155)
  • loss of 53% of corticospinal, 41% of bulbospinal and 43% of rubrospinal neurons at 110 days
  (MGI Ref ID J:133155)
  • progressive loss of upper motor neurons
  (MGI Ref ID J:133155)

• motor neuron degeneration
  • swollen and degenerating motor neurons in the late stage in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • intracellular edema in some motor neurons, characterized by cytoplasmic enlargement
  (MGI Ref ID J:165019)
  • vacuolization and silver-impregnated neurites at 2 months of age in the spinal cord, proceed caudocranially into the brain and reach telencephalic regions at 5 months of age
  (MGI Ref ID J:110437)

• brain vacuoles
  • increased number of vacuoles in the brainstem nuclei from Day 80 onwards
  (MGI Ref ID J:127265)
  • continuous age-dependent increased number of vacuoles
  (MGI Ref ID J:127265)
  • vacuolization in the brain and reach telencephalic regions at 5 months of age
  (MGI Ref ID J:110437)

• abnormal cerebral cortex morphology
  • degenerative pyramidal-shaped neurons and several long neurites in motor as well as in extra-motor areas of the cerebral cortex at 5 months of age
  (MGI Ref ID J:110437)

• abnormal corticospinal tract morphology
  • progressive loss of corticospinal tract neurons (9% at 60 days, 30% at 90 days and 53% at 110 days)
  (MGI Ref ID J:133155)
  • progressive loss of dorsal corticospinal axons (13% at 60 days, 22% at 90 days and 32% at 110 days)
  (MGI Ref ID J:133155)

• abnormal microglial cell morphology
  • increased cell size starting at day 100
  (MGI Ref ID J:143173)
  • large vacuoles in microglial cell cytoplasm in the cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • increased granularity starting at day 100
  (MGI Ref ID J:143173)

• abnormal tegmentum morphology
  • degeneration lesions in the neuropil of the ventral tegmental field
  (MGI Ref ID J:110437)

• abnormal thalamus morphology
  • degeneration lesions in the nucleus anterior thalami
  (MGI Ref ID J:110437)

• abnormal red nucleus morphology
  • spongio-form degenerative changes in the red nucleus
  (MGI Ref ID J:110437)

• microgliosis
  • first noted at 6 weeks
  (MGI Ref ID J:146652)
  • increase in the number of glial processes abutting onto the neuronal surface and apposed to the presynaptic terminal in 10-week-old and 18-week-old mice
  (MGI Ref ID J:146652)
  • microglia (CD11b+ CD45lo) population expanded 1.65-fold by day 135 in spinal cords
  (MGI Ref ID J:143173)
  • some microglial cells occupy areas where formerly occupied by astrocytes or oligodendrocytes in the cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • appear simultaneously to the degenerative changes and increase substantially with time
  (MGI Ref ID J:110437)

• abnormal axonal transport
  • increased number of retrograde mitochondria by around 80% after fast axonal transport (FAT)
  (MGI Ref ID J:129976)
  • decreased fraction of anterograde mitochondria
  (MGI Ref ID J:129976)

• abnormal hypothalamus morphology
  • degenerative changes in the hypothalamic nuclei at 5 months of age
  (MGI Ref ID J:110437)

• CNS inflammation
  • later in the degenerating regions up to the mesencephalon
  (MGI Ref ID J:110437)
  • lymphocytes and CD11c positive dendritic cells infiltrate the affected CNS regions not before 4 months of age
  (MGI Ref ID J:110437)
  • first in the spinal cord, predominantly in the white matter
  (MGI Ref ID J:110437)

• abnormal globus pallidus morphology
  • degenerative changes in the globus pallidus at 5 months of age
  (MGI Ref ID J:110437)

• astrocytosis
  • appear simultaneously to the degenerative changes and increase substantially with time
  (MGI Ref ID J:110437)

• abnormal brain morphology
  • degenerating somata in the brain at 4 months of age
  (MGI Ref ID J:110437)

• abnormal midbrain morphology
  • degeneration lesions in the retrorubral field
  (MGI Ref ID J:110437)

• abnormal spinal cord ventral horn morphology
  • most ventral horn motor neurons lack autofluorescent lipofuscin in cell bodies at 3 months of age
  (MGI Ref ID J:212250)

behavior/neurological phenotype

• increased anxiety-related response
  • slightly increased anxiety-related behavior
  (MGI Ref ID J:110437)
  • reduced mean time spent in the center of the open field from 4 months on
  (MGI Ref ID J:110437)

• tremors
  • hind limb tremors at 14 weeks of age
  (MGI Ref ID J:138237)
  • mild hindlimb tremor at 90 days of age
  (MGI Ref ID J:146652)

• abnormal drinking behavior
  • progressive decrease in lick rhythm over time beginning at approximately 102 days of age
  (MGI Ref ID J:130811)

• abnormal motor capabilities/coordination/movement
  (MGI Ref ID J:130811)

• decreased grip strength
  • reduced muscle strength in this traction test even from the age of 35 days
  (MGI Ref ID J:103582)
  • progressive reduced forelimb and hindlimb grip force from the onset of testing (64 days of age)
  (MGI Ref ID J:130811)

• hindlimb paralysis
  • dragging in one hindlimb and inability to grasp a cage bar at 103 days of age
  (MGI Ref ID J:146652)
  • first signs of hindlimb paralysis at 3.5-5 months of age
  (MGI Ref ID J:110437)
  • paralysis progresses to both hindlimbs within 3-4 days
  (MGI Ref ID J:146652)

• impaired coordination
  • lower performance rate (<90%) in rotarod test from 71 days of age
  (MGI Ref ID J:130811)
  • failed rotarod test after 113 days of age
  (MGI Ref ID J:130811)

• hypoactivity
  • progressively decreased overall motor activity during the first 3 months
  (MGI Ref ID J:110437)
  • lower horizontal travel distance and number of stops at 3.5 months of age in open field analysis
  (MGI Ref ID J:110437)
  • longer duration of stops at 3.5-4.5 months of age
  (MGI Ref ID J:110437)

cardiovascular system phenotype

• abnormal vascular endothelial cell morphology
  • characterized by mitochondrial damage, swelling of endoplasmic reticulum, cytoplasmic vacuolization and cell death
  (MGI Ref ID J:165019)
  • progressive swollen and degenerating capillary endothelial cells in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • endothelial cell membrane and/or basement membrane damage, followed by vascular leakage
  (MGI Ref ID J:165019)

• abnormal capillary morphology
  • disruption of blood-brain barrier and blood-spinal cord barrier in areas of motor neuron degeneration in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • multiple layers of endothelial cells separated by sheets of basement membrane material
  (MGI Ref ID J:165019)
  • intracellular edema, endoplasmic reticulum swelling and formation of numerous large vacuoles in capillary endothelial cells cytoplasm
  (MGI Ref ID J:165019)
  • pericytes under the capillary basement membrane
  (MGI Ref ID J:165019)

cellular phenotype

• abnormal cell physiology
  • decreased glutamate uptake in synaptosomes at 150 days of age
  (MGI Ref ID J:103582)
  • decreased velocity of anterograde transport
  (MGI Ref ID J:129976)
  • normal retrograde frequency
  (MGI Ref ID J:129976)
  • decreased anterograde frequency by almost 60% for the activity of mitochondrial molecular motors
  (MGI Ref ID J:129976)
  • normal overall level of activity of mitochondrial molecular motors
  (MGI Ref ID J:129976)
  • reduced persistence of movement in the anterograde direction
  (MGI Ref ID J:129976)
  • normal velocity of retrograde transport
  (MGI Ref ID J:129976)

• abnormal endoplasmic reticulum morphology
  • dilation of the endoplasmic reticulum in motor neuron cytoplasm in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • rER damage appearing as 'splits' in the cytoplasm by 18 weeks
  (MGI Ref ID J:146652)
  • dilated Golgi-ER and less organized, with increased numbers of separated highly dilated ER profiles
  (MGI Ref ID J:146652)
  • Nissl body rough ERs (rER) in the terminals appear more prominent, with evidence of polyribosomal hyperplasia at 10 weeks of age
  (MGI Ref ID J:146652)

• abnormal mitochondrial morphology
  • disorganized mitochondrial cristae and degenerating mitochondria in astrocytes, capillary endothelial cells and neuropil in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • characterized by swelling, cristae disruption and eventual vacuolization of mitochondria
  (MGI Ref ID J:165019)

• abnormal mitochondrial physiology
  • loss of mitochondrial inner membrane potential in fiber segments near the neuromuscular junction starting at the age of 37 days
  (MGI Ref ID J:158298)

• increased mitochondrial size
  • enlarged mitochondria with vacuoles, invading the sarcomeric A band
  (MGI Ref ID J:158298)

• abnormal mitochondrial crista morphology
  • reduced numbers of short, 'broken' cristae in the terminals at 10 weeks of age
  (MGI Ref ID J:146652)

• abnormal mitochondrial shape
  • lower aspect ratio showing rounding up mitochondria
  (MGI Ref ID J:129976)

• dilated mitochondria
  • swollen mitochondria
  (MGI Ref ID J:146652)

• abnormal respiratory electron transport chain
  • reduced mitochondrial electron transport activity
  (MGI Ref ID J:129976)

growth/size/body region phenotype

• slow postnatal weight gain
  • no weight gain beginning at approximately 108 days of age
  (MGI Ref ID J:130811)

hematopoietic system phenotype

• decreased lymphocyte cell number
  • lower lymphocyte density
  (MGI Ref ID J:129215)

• decreased monocyte cell number
  • decreased number of circulating monocytes
  (MGI Ref ID J:129215)

• small spleen
  • reduced spleen size at end stage (20-22 weeks of age)
  (MGI Ref ID J:138237)

• abnormal splenic cell ratio
  • increased levels of CD45RO+ (memory) T cells
  (MGI Ref ID J:138237)
  • decreased levels of CD45RA+ (naive) T cells
  (MGI Ref ID J:138237)

• abnormal microglial cell morphology
  • increased granularity starting at day 100
  (MGI Ref ID J:143173)
  • large vacuoles in microglial cell cytoplasm in the cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • increased cell size starting at day 100
  (MGI Ref ID J:143173)

• decreased leukocyte cell number
  • reduced WBC numbers
  (MGI Ref ID J:129215)
  • Normal - normal neutrophil levels
  (MGI Ref ID J:129215)

• microgliosis
  • appear simultaneously to the degenerative changes and increase substantially with time
  (MGI Ref ID J:110437)
  • microglia (CD11b+ CD45lo) population expanded 1.65-fold by day 135 in spinal cords
  (MGI Ref ID J:143173)
  • some microglial cells occupy areas where formerly occupied by astrocytes or oligodendrocytes in the cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • first noted at 6 weeks
  (MGI Ref ID J:146652)
  • increase in the number of glial processes abutting onto the neuronal surface and apposed to the presynaptic terminal in 10-week-old and 18-week-old mice
  (MGI Ref ID J:146652)

• abnormal lymphocyte morphology
  • a number of lymphocytes spontaneously form rosettes with autologous erythrocytes in two thirds of the mice
  (MGI Ref ID J:129215)

• increased basophil cell number
  • increased basophil number compared with Tg(SOD1)2Gur mice
  (MGI Ref ID J:129215)

• abnormal spleen morphology
  • diminished follicular architecture with a greater number of follicles at end stage
  (MGI Ref ID J:138237)

• abnormal splenocyte morphology
  • increased annexin-V associated apoptosis and necrosis of lymphocytes at pre-symptomatic stage (14 weeks of age)
  (MGI Ref ID J:138237)

• decreased eosinophil cell number
  • decreased number of circulating eosinophils
  (MGI Ref ID J:129215)

• decreased spleen weight
  • reduced spleen weight (45%) at 19 weeks of age
  (MGI Ref ID J:138237)

homeostasis/metabolism phenotype

• abnormal glucose homeostasis
  • reductions in glucose use in the gray matter of cervical, thoracic, or lumbar regions of the spinal cord in 120-day-old mice
  (MGI Ref ID J:111280)
  • impaired glucose utilization rates in multiple brain components of the motor system as early as 60 days of age
  (MGI Ref ID J:111280)
  • components of the bulbospinal projection pathway are compromised by 60 days of age, whereas rubrospinal projections become involved later
  (MGI Ref ID J:111280)

• abnormal calcium ion homeostasis
  • greater osmotic stress-induced Ca²⁺ release activity in fiber segments with depolarized mitochondria
  (MGI Ref ID J:158298)

• edema
  • progressive edema in the brainstem, cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • characterized by the formation of protein-filled areas in the extracellular space formerly occupied by astrocytes or neuropil
  (MGI Ref ID J:165019)

immune system phenotype

• abnormal splenocyte morphology
  • increased annexin-V associated apoptosis and necrosis of lymphocytes at pre-symptomatic stage (14 weeks of age)
  (MGI Ref ID J:138237)

• microgliosis
  • appear simultaneously to the degenerative changes and increase substantially with time
  (MGI Ref ID J:110437)
  • increase in the number of glial processes abutting onto the neuronal surface and apposed to the presynaptic terminal in 10-week-old and 18-week-old mice
  (MGI Ref ID J:146652)
  • first noted at 6 weeks
  (MGI Ref ID J:146652)
  • microglia (CD11b+ CD45lo) population expanded 1.65-fold by day 135 in spinal cords
  (MGI Ref ID J:143173)
  • some microglial cells occupy areas where formerly occupied by astrocytes or oligodendrocytes in the cervical and lumbar spinal cord
  (MGI Ref ID J:165019)

• CNS inflammation
  • first in the spinal cord, predominantly in the white matter
  (MGI Ref ID J:110437)
  • later in the degenerating regions up to the mesencephalon
  (MGI Ref ID J:110437)
  • lymphocytes and CD11c positive dendritic cells infiltrate the affected CNS regions not before 4 months of age
  (MGI Ref ID J:110437)

• decreased leukocyte cell number
  • reduced WBC numbers
  (MGI Ref ID J:129215)
  • Normal - normal neutrophil levels
  (MGI Ref ID J:129215)

• decreased lymphocyte cell number
  • lower lymphocyte density
  (MGI Ref ID J:129215)

• decreased spleen weight
  • reduced spleen weight (45%) at 19 weeks of age
  (MGI Ref ID J:138237)

• small spleen
  • reduced spleen size at end stage (20-22 weeks of age)
  (MGI Ref ID J:138237)

• abnormal microglial cell morphology
  • increased cell size starting at day 100
  (MGI Ref ID J:143173)
  • large vacuoles in microglial cell cytoplasm in the cervical and lumbar spinal cord
  (MGI Ref ID J:165019)
  • increased granularity starting at day 100
  (MGI Ref ID J:143173)

• decreased monocyte cell number
  • decreased number of circulating monocytes
  (MGI Ref ID J:129215)

• abnormal spleen morphology
  • diminished follicular architecture with a greater number of follicles at end stage
  (MGI Ref ID J:138237)

• abnormal splenic cell ratio
  • decreased levels of CD45RA+ (naive) T cells
  (MGI Ref ID J:138237)
  • increased levels of CD45RO+ (memory) T cells
  (MGI Ref ID J:138237)

• decreased eosinophil cell number
  • decreased number of circulating eosinophils
  (MGI Ref ID J:129215)

• increased basophil cell number
  • increased basophil number compared with Tg(SOD1)2Gur mice
  (MGI Ref ID J:129215)

• abnormal lymphocyte morphology
  • a number of lymphocytes spontaneously form rosettes with autologous erythrocytes in two thirds of the mice
  (MGI Ref ID J:129215)

mortality/aging

• premature death
  • Background Sensitivity - decreased survival on SJL/J background (119.2¿9.7 days) in contrast to B6SJL/J background (130.2¿11.2 days)
  (MGI Ref ID J:128550)
  • survive from 16-20 weeks
  (MGI Ref ID J:138237)
  • survival in male mice ranges between 105 days and 127 days
  (MGI Ref ID J:146652)
  • female mice survive longer than the male on B6SJL/J (132.8¿12.4 vs. 127.9¿9.5 days) and SJL/J (122.5¿10.9 vs. 115.2¿6.2 days) background
  (MGI Ref ID J:128550)
  • survival is 157.2 ¿ 2.2 days
  (MGI Ref ID J:103582)

mortality/aging

• premature death
  • Background Sensitivity - mice on a background containing ABH exhibit shorter life span than mice on a mixed C57BL/6 and SJL background
  (MGI Ref ID J:111498)

nervous system phenotype

• decreased neuron number
  • decreased number of total neurons within the ventral horns of the lumbar cord at 110 days of age
  (MGI Ref ID J:62381)

• decreased spinal cord ventral horn cell number
  • decreased number of total neurons within the ventral horns of the lumbar cord at 110 days of age
  (MGI Ref ID J:62381)

• decreased substantia nigra size
  • decreased number of total neurons within the substatia nigra at 110 days of age
  (MGI Ref ID J:62381)

behavior/neurological phenotype

• tremors
  • in only 3 of 11 mice
  (MGI Ref ID J:97818)
  • onset at 185¿6.3 days
  (MGI Ref ID J:97818)

growth/size/body region phenotype

• weight loss
  • declined body weight (12% over 64 days) after 20 weeks of age
  (MGI Ref ID J:97818)

mortality/aging

• premature death
  • decreased survival (208.4¿5.06 vs. >350 days), compared with wild-type mice
  (MGI Ref ID J:97818)

behavior/neurological phenotype

• decreased grip strength
  • deficits in paw grip endurance test (PaGE)
  (MGI Ref ID J:155140)
  • delayed chronic deficits in female compared to male
  (MGI Ref ID J:155140)

• decreased vertical activity
  • deficits in all four open-field performance measures start earlier than the conventional PaGE or rotarod tests
  (MGI Ref ID J:155140)
  • decreased average locomotion velocity and rearing episodes
  (MGI Ref ID J:155140)
  • motor deficits in rearing episodes beginning at P45
  (MGI Ref ID J:155140)
  • persist at each subsequent time point up to and beyond the onset of overt clinical symptoms
  (MGI Ref ID J:155140)
  • delayed chronic deficits in average velocity in female compared to male
  (MGI Ref ID J:155140)
  • significant motor deficits in male and female mice (at P45 and P65 respectively) in average locomotion velocity
  (MGI Ref ID J:155140)

• hypoactivity
  • transient or no deficits in ambulatory distance and rest behaviors, respectively in female
  (MGI Ref ID J:155140)
  • motor deficits in ambulatory distance and resting time in male mice beginning at P45
  (MGI Ref ID J:155140)

• tremors
  • tremor onset occurred significantly sooner in male (91¿2 days) compared to female (100¿2 days)
  (MGI Ref ID J:155140)

• impaired coordination
  • deficits in rotarod test
  (MGI Ref ID J:155140)

growth/size/body region phenotype

• decreased body weight
  • decreased body weight starting at P65
  (MGI Ref ID J:155140)

mortality/aging

• premature death
  • mean survivals in male and female mice are 153 ¿ 2 and 161¿ 2 days respectively
  (MGI Ref ID J:155140)

muscle phenotype

• decreased skeletal muscle size
  • smaller hindlimb thigh girth medial/lateral starting at P75
  (MGI Ref ID J:155140)
  • smaller hindlimb calf girth medial/lateral starting at P65
  (MGI Ref ID J:155140)
  • smaller hindlimb calf girth dorsal/ventral (d/v) starting at P55
  (MGI Ref ID J:155140)
  • calf (d/v) and thigh muscle girth are able to predict genotype in pre-symptomatic animals with 80% or greater accuracy (about 40 day prior to tremor onset)
  (MGI Ref ID J:155140)

immune system phenotype

• abnormal spleen morphology
  • diminished follicular area by 67% with a greater number (41%) of follicles at end stage
  (MGI Ref ID J:138237)

• decreased spleen weight
  • reduced spleen weight (59%) at 22 weeks of age
  (MGI Ref ID J:138237)

• decreased splenocyte number
  • reduced viable spleen cell numbers (70%) at 22 weeks of age
  (MGI Ref ID J:138237)

• abnormal T cell physiology
  • progressively diminished proliferative capacity of T cells with age
  (MGI Ref ID J:138237)

mortality/aging

• premature death
  • Background Sensitivity - increased survival on C57BL/6J background (143.6+/-7.5 days) in contrast to B6SJL/J background (130.2+/-11.2 days)
  (MGI Ref ID J:128550)
  • average lifespan is 171.8 days
  (MGI Ref ID J:211734)
  • increased survival by weekly immunization with Copolymer-1 (9.9%) in female mice
  (MGI Ref ID J:138237)
  • mean time from onset of tremors to death is 16.5 +/-9.3 days
  (MGI Ref ID J:115355)
  • reconstitution with Treg delays neurological symptom onset
  (MGI Ref ID J:138237)
  • die within 10+/-0.6 days of clinical disease onset
  (MGI Ref ID J:95812)
  • disease onset at 111+/-1.8 days
  (MGI Ref ID J:95812)
  • reconstitution with polyclonal-activated Treg and Teff subsets delays loss of motor function and extends survival
  (MGI Ref ID J:138237)
  • survive from 19-22 weeks
  (MGI Ref ID J:138237)
  • reconstitution with Teff increases latency between disease onset and entry into late stage
  (MGI Ref ID J:138237)
  • 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)
  (MGI Ref ID J:115355)
  • maximal life span of 145 days
  (MGI Ref ID J:95812)

behavior/neurological phenotype

• impaired coordination
  • mice show impaired performance on the rotarod and in hanging from a grid
  (MGI Ref ID J:211734)

• long stride length
  (MGI Ref ID J:138237)

• tremors
  • hind limb tremors at 14 weeks of age
  (MGI Ref ID J:138237)
  • observed hindlimb tremors when suspended by tail at 142.3 +/- 10.6 days (approx. 20 weeks)
  (MGI Ref ID J:115355)

• abnormal gait
  • exhibited longer stride and stance times as compared to C57BL/6J controls, however swing time difference was not significant
  (MGI Ref ID J:115355)

muscle phenotype

• decreased skeletal muscle fiber diameter
  • severe muscle atrophy at 123 d
  (MGI Ref ID J:95812)
  • at 112 d and 123 d compared with wild-type mice
  (MGI Ref ID J:95812)

• abnormal skeletal muscle fiber type ratio
  • altered fiber type composition at 80 d with a shift toward a fast fiber type
  (MGI Ref ID J:95812)

nervous system phenotype

• decreased motor neuron number
  • progressive reduction in the number of motor neuron from clinical onset to end-stage disease
  (MGI Ref ID J:95812)
  • a reduction of 37 and 55% in the number of motor neurons at clinical onset (112 d) and at end-stage disease (123 d), respectively
  (MGI Ref ID J:95812)

• motor neuron degeneration
  • average onset of motor neuron degeneration is 137.4 days
  (MGI Ref ID J:211734)

hematopoietic system phenotype

• abnormal T cell physiology
  • progressively diminished proliferative capacity of T cells with age
  (MGI Ref ID J:138237)

• decreased splenocyte number
  • reduced viable spleen cell numbers (70%) at 22 weeks of age
  (MGI Ref ID J:138237)

• decreased spleen weight
  • reduced spleen weight (59%) at 22 weeks of age
  (MGI Ref ID J:138237)

• abnormal spleen morphology
  • diminished follicular area by 67% with a greater number (41%) of follicles at end stage
  (MGI Ref ID J:138237)