Phenotypes Associated with This Genotype

Genotype
MGI:4822033

• Allelic Composition: Tg(SOD1*G93A)1Gur/0
• Genetic Background: B6SJL-Tg(SOD1*G93A)1Gur/J

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

Structural and functional defects of mitochondria in Tg(SOD1*G93A)1Gur/0 muscle

mortality/aging

premature death ( J:103582 , J:128550 , J:138237 , J:146652 )

• survival is 157.2 2.2 days (J:103582)

• Background Sensitivity: decreased survival on SJL/J background (119.29.7 days) in contrast to B6SJL/J background (130.211.2 days) (J:128550)

• female mice survive longer than the male on B6SJL/J (132.812.4 vs. 127.99.5 days) and SJL/J (122.510.9 vs. 115.26.2 days) background (J:128550)

• survive from 16-20 weeks (J:138237)

• survival in male mice ranges between 105 days and 127 days (J:146652)

behavior/neurological

abnormal drinking behavior ( J:130811 )

• progressive decrease in lick rhythm over time beginning at approximately 102 days of age

increased anxiety-related response ( J:110437 )

• slightly increased anxiety-related behavior

• reduced mean time spent in the center of the open field from 4 months on

abnormal motor capabilities/coordination/movement ( J:130811 )

tremors ( J:138237 , J:146652 )

• hind limb tremors at 14 weeks of age (J:138237)

• mild hindlimb tremor at 90 days of age (J:146652)

impaired coordination ( J:130811 )

• lower performance rate (<90%) in rotarod test from 71 days of age

• failed rotarod test after 113 days of age

decreased grip strength ( J:103582 , J:130811 )

• reduced muscle strength in this traction test even from the age of 35 days (J:103582)

• progressive reduced forelimb and hindlimb grip force from the onset of testing (64 days of age) (J:130811)

decreased locomotor activity ( J:110437 )

• progressively decreased overall motor activity during the first 3 months

• lower horizontal travel distance and number of stops at 3.5 months of age in open field analysis

• longer duration of stops at 3.5-4.5 months of age

hindlimb paralysis ( J:110437 , J:146652 )

• first signs of hindlimb paralysis at 3.5-5 months of age (J:110437)

• dragging in one hindlimb and inability to grasp a cage bar at 103 days of age (J:146652)

• paralysis progresses to both hindlimbs within 3-4 days (J:146652)

nervous system

abnormal microglial cell morphology ( J:143173 , J:165019 )

• increased cell size starting at day 100 (J:143173)

• increased granularity starting at day 100 (J:143173)

• large vacuoles in microglial cell cytoplasm in the cervical and lumbar spinal cord (J:165019)

microgliosis ( J:110437 , J:143173 , J:146652 , J:165019 )

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

• microglia (CD11b+ CD45lo) population expanded 1.65-fold by day 135 in spinal cords (J:143173)

• 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 (J:146652)

• first noted at 6 weeks (J:146652)

• some microglial cells occupy areas where formerly occupied by astrocytes or oligodendrocytes in the cervical and lumbar spinal cord (J:165019)

abnormal brain morphology ( J:110437 )

• degenerating somata in the brain at 4 months of age

abnormal brainstem morphology ( J:110437 , J:127265 )

• 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 (J:110437)

• vacuoles in the trigeminal nucleus and the locus coeruleus neuropil at 3 months of age (J:110437)

• degeneration of brainstem motor nuclei (the trigeminal, hypoglossal and facial nucleus as early as Day 80 by magnetic resonance imaging (MRI) (J:127265)

• higher relaxation parameter T2 values for all the three brainstem nuclei after 80 days (J:127265)

• continuous age-dependent T2 values increase (J:127265)

• increased area of the brainstem nuclei (hypoglossal and facial nucleus) between 80 and 120 days after birth (J:127265)

• H&E staining with brain sections show same morphological alterations (J:127265)

• increased number of vacuoles in the brainstem nuclei from Day 80 onwards (J:127265)

• continuous age-dependent increased number of vacuoles (J:127265)

abnormal midbrain morphology ( J:110437 )

• degeneration lesions in the retrorubral field

abnormal superior colliculus morphology ( J:110437 )

• degeneration lesions in the deep layers of the colliculi superior

abnormal oculomotor nucleus morphology ( J:110437 )

• heavily filled with Gallyas+, coiled and ballooned axonal and dendritic profiles in the oculomotor ,the trochlear nucleus at 4 months of age

abnormal substantia nigra morphology ( J:110437 )

• degeneration lesions in the substantia nigra

abnormal tegmentum morphology ( J:110437 )

• degeneration lesions in the neuropil of the ventral tegmental field

abnormal red nucleus morphology ( J:110437 )

• spongio-form degenerative changes in the red nucleus

abnormal globus pallidus morphology ( J:110437 )

• degenerative changes in the globus pallidus at 5 months of age

abnormal hypothalamus morphology ( J:110437 )

• degenerative changes in the hypothalamic nuclei at 5 months of age

abnormal thalamus morphology ( J:110437 )

• degeneration lesions in the nucleus anterior thalami

abnormal cerebral cortex morphology ( J:110437 )

• 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

brain vacuoles ( J:110437 , J:127265 )

• vacuolization in the brain and reach telencephalic regions at 5 months of age (J:110437)

• increased number of vacuoles in the brainstem nuclei from Day 80 onwards (J:127265)

• continuous age-dependent increased number of vacuoles (J:127265)

abnormal astrocyte morphology ( J:165019 )

• swollen, progressive degeneration of astrocytes in the brainstem, cervical and lumbar spinal cord

• characterized by mitochondrial damage, cellular edema and cell rupture

astrocytosis ( J:110437 )

• appear simultaneously to the degenerative changes and increase substantially with time

abnormal corticospinal tract morphology ( J:133155 )

• progressive loss of corticospinal tract neurons (9% at 60 days, 30% at 90 days and 53% at 110 days)

• progressive loss of dorsal corticospinal axons (13% at 60 days, 22% at 90 days and 32% at 110 days)

abnormal synaptic bouton morphology ( J:146652 )

• degenerative changes occurred in all classes of terminal at 6, 10 and 18 weeks of age, apart from the C-type terminal

• thin glial processes either partly or totally engulfed some terminals at 18 weeks of age

• reduction in both terminal number and coverage of the somal membrane, and decline further by around 60% at 18 weeks of age

• increase in the proportional numbers of C-terminals at 6 and 18 weeks of age

• increase in the membrane coverage of C-terminals at 6, 10 and 18 weeks of age

• progressive enlargement of the C-terminal presynaptic terminal at 10 and 18 weeks of age

• increased size of the postsynaptic structure of C-terminals

• increased length of the subsynaptic cistern of C-terminals

• increased number of the Nissl body rER lamellae of C-terminals at 18 weeks of age

• increased overall length of the Nissl body rER lamellae of C-terminals at 10 and 18 weeks of age

abnormal spinal cord morphology ( J:110437 , J:143173 )

• swollen neurites and vacuoles of various dimensions and large neuritic spheroids in some spinal motor neurons at the age of 2 months (J:110437)

• restricted to the ventral horns of spinal cords at the age of 2 months (J:110437)

• increase and extend into the dorsal horn of the spinal cord within the following month (J:110437)

• increased lymphocyte population in spinal cords at day 65 (J:143173)

• increase with disease progression, 36-fold by day 135 (J:143173)

• significant accumulation of CD4+ and CD8+ T cells in spinal cords (J:143173)

• natural killer cell in spinal cords (J:143173)

abnormal motor neuron morphology ( J:129976 , J:146652 , J:165019 , J:212250 )

• increased mitochondria in cell bodies of motoneurons (J:129976)

• decreased mitochondria in axonal mitochondria (J:129976)

• increased intermitochondrial distance by 30-50% in axons (J:129976)

• paler and more strongly stained motoneurons, with vacuolation in the more strongly stained motoneurons by 6 weeks (J:146652)

• more electron-lucent than electron-dense motoneurons by 18 weeks, and many motoneurons exhibit extensive vacuolation (J:146652)

• large membrane bound vacuoles consisting of either dilated axons or dendrite (J:165019)

• mitochondria with swollen cristae in both axons and dendrites near capillaries (J:165019)

• most ventral horn motor neurons lack autofluorescent lipofuscin in cell bodies at 3 months of age (J:212250)

• however, lipofuscin is detected in the neuron cell bodies of the dorsal regions of the spinal cord gray matter (J:212250)

decreased motor neuron number ( J:133155 )

• progressive loss of upper motor neurons

• small loss of corticospinal (9%), bulbospinal (12%) and rubrospinal (14%) projections at 60 days

• loss of 30% of corticospinal, 33% of bulbospinal and 33% of rubrospinal neurons at 90 days

• loss of 53% of corticospinal, 41% of bulbospinal and 43% of rubrospinal neurons at 110 days

motor neuron degeneration ( J:110437 , 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 (J:110437)

• swollen and degenerating motor neurons in the late stage in the brainstem, cervical and lumbar spinal cord (J:165019)

• intracellular edema in some motor neurons, characterized by cytoplasmic enlargement (J:165019)

abnormal spinal cord ventral horn morphology ( J:212250 )

• most ventral horn motor neurons lack autofluorescent lipofuscin in cell bodies at 3 months of age

abnormal nervous system physiology ( J:111280 )

• lower basal ATP levels in cerebral cortex in 30-day-old mice

• the extent of impairment in ATP production progresses with age

• partially ameliorated by creatine administration

• reduced ADP levels by 60 days of age

• reduced creatine levels by 90 days of age in both cerebral cortex and spinal cord

CNS inflammation ( J:110437 )

• lymphocytes and CD11c positive dendritic cells infiltrate the affected CNS regions not before 4 months of age

• first in the spinal cord, predominantly in the white matter

• later in the degenerating regions up to the mesencephalon

abnormal axonal transport ( J:129976 )

• increased number of retrograde mitochondria by around 80% after fast axonal transport (FAT)

• decreased fraction of anterograde mitochondria

cellular

abnormal endoplasmic reticulum morphology ( J:146652 , J:165019 )

• Nissl body rough ERs (rER) in the terminals appear more prominent, with evidence of polyribosomal hyperplasia at 10 weeks of age (J:146652)

• dilated Golgi-ER and less organized, with increased numbers of separated highly dilated ER profiles (J:146652)

• rER damage appearing as 'splits' in the cytoplasm by 18 weeks (J:146652)

• dilation of the endoplasmic reticulum in motor neuron cytoplasm in the brainstem, cervical and lumbar spinal cord (J:165019)

abnormal mitochondrial morphology ( J:165019 )

• characterized by swelling, cristae disruption and eventual vacuolization of mitochondria

• disorganized mitochondrial cristae and degenerating mitochondria in astrocytes, capillary endothelial cells and neuropil in the brainstem, cervical and lumbar spinal cord

abnormal mitochondrial crista morphology ( J:146652 )

• reduced numbers of short, 'broken' cristae in the terminals at 10 weeks of age

abnormal mitochondrial shape ( J:129976 )

• lower aspect ratio showing rounding up mitochondria

increased mitochondrial size ( J:158298 )

• enlarged mitochondria with vacuoles, invading the sarcomeric A band

dilated mitochondrion ( J:146652 )

• swollen mitochondria

abnormal cell physiology ( J:103582 , J:129976 )

• decreased glutamate uptake in synaptosomes at 150 days of age (J:103582)

• decreased anterograde frequency by almost 60% for the activity of mitochondrial molecular motors (J:129976)

• decreased velocity of anterograde transport (J:129976)

• reduced persistence of movement in the anterograde direction (J:129976)

• normal retrograde frequency (J:129976)

• normal overall level of activity of mitochondrial molecular motors (J:129976)

• normal velocity of retrograde transport (J:129976)

abnormal mitochondrial physiology ( J:158298 )

• loss of mitochondrial inner membrane potential in fiber segments near the neuromuscular junction starting at the age of 37 days

abnormal respiratory electron transport chain ( J:129976 )

• reduced mitochondrial electron transport activity

homeostasis/metabolism

edema ( J:165019 )

• progressive edema in the brainstem, cervical and lumbar spinal cord

• characterized by the formation of protein-filled areas in the extracellular space formerly occupied by astrocytes or neuropil

abnormal glucose homeostasis ( J:111280 )

• impaired glucose utilization rates in multiple brain components of the motor system as early as 60 days of age

• components of the bulbospinal projection pathway are compromised by 60 days of age, whereas rubrospinal projections become involved later

• reductions in glucose use in the gray matter of cervical, thoracic, or lumbar regions of the spinal cord in 120-day-old mice

abnormal calcium ion homeostasis ( J:158298 )

• greater osmotic stress-induced Ca²⁺ release activity in fiber segments with depolarized mitochondria

muscle

abnormal skeletal muscle fiber morphology ( J:158298 )

• enlarged mitochondria with vacuoles, invading the sarcomeric A band

abnormal muscle physiology ( J:158298 )

• greater osmotic stress-induced Ca²⁺ release activity in fiber segments with depolarized mitochondria

muscle weakness ( J:130811 )

• progressive decrease in tongue force beginning at approximately 113 days of age

• progressive reduced forelimb and hindlimb grip force from the onset of testing (64 days of age)

progressive muscle weakness ( J:103582 , J:146652 )

• after 120 days of age (J:103582)

• dragging in one hindlimb and inability to grasp a cage bar at 103 days of age (J:146652)

• paralysis progresses to both hindlimbs within 3-4 days (J:146652)

immune system

increased basophil cell number ( J:129215 )

• increased basophil number compared with Tg(SOD1)2Gur mice

decreased leukocyte cell number ( J:129215 )

• reduced WBC numbers

• normal neutrophil levels

decreased eosinophil cell number ( J:129215 )

• decreased number of circulating eosinophils

decreased monocyte cell number ( J:129215 )

• decreased number of circulating monocytes

abnormal lymphocyte morphology ( J:129215 )

• a number of lymphocytes spontaneously form rosettes with autologous erythrocytes in two thirds of the mice

decreased lymphocyte cell number ( J:129215 )

• lower lymphocyte density

abnormal microglial cell morphology ( J:143173 , J:165019 )

• increased cell size starting at day 100 (J:143173)

• increased granularity starting at day 100 (J:143173)

• large vacuoles in microglial cell cytoplasm in the cervical and lumbar spinal cord (J:165019)

microgliosis ( J:110437 , J:143173 , J:146652 , J:165019 )

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

• microglia (CD11b+ CD45lo) population expanded 1.65-fold by day 135 in spinal cords (J:143173)

• 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 (J:146652)

• first noted at 6 weeks (J:146652)

• some microglial cells occupy areas where formerly occupied by astrocytes or oligodendrocytes in the cervical and lumbar spinal cord (J:165019)

abnormal spleen morphology ( J:138237 )

• diminished follicular architecture with a greater number of follicles at end stage

small spleen ( J:138237 )

• reduced spleen size at end stage (20-22 weeks of age)

decreased spleen weight ( J:138237 )

• reduced spleen weight (45%) at 19 weeks of age

abnormal splenic cell ratio ( J:138237 )

• decreased levels of CD45RA+ (naive) T cells

• increased levels of CD45RO+ (memory) T cells

abnormal splenocyte morphology ( J:138237 )

• increased annexin-V associated apoptosis and necrosis of lymphocytes at pre-symptomatic stage (14 weeks of age)

CNS inflammation ( J:110437 )

• lymphocytes and CD11c positive dendritic cells infiltrate the affected CNS regions not before 4 months of age

• first in the spinal cord, predominantly in the white matter

• later in the degenerating regions up to the mesencephalon

growth/size/body

slow postnatal weight gain ( J:130811 )

• no weight gain beginning at approximately 108 days of age

cardiovascular system

abnormal vascular endothelial cell morphology ( J:165019 )

• characterized by mitochondrial damage, swelling of endoplasmic reticulum, cytoplasmic vacuolization and cell death

• endothelial cell membrane and/or basement membrane damage, followed by vascular leakage

• progressive swollen and degenerating capillary endothelial cells in the brainstem, cervical and lumbar spinal cord

abnormal capillary morphology ( J:165019 )

• disruption of blood-brain barrier and blood-spinal cord barrier in areas of motor neuron degeneration in the brainstem, cervical and lumbar spinal cord

• pericytes under the capillary basement membrane

• intracellular edema, endoplasmic reticulum swelling and formation of numerous large vacuoles in capillary endothelial cells cytoplasm

• multiple layers of endothelial cells separated by sheets of basement membrane material

hematopoietic system

increased basophil cell number ( J:129215 )

• increased basophil number compared with Tg(SOD1)2Gur mice

decreased leukocyte cell number ( J:129215 )

• reduced WBC numbers

• normal neutrophil levels

decreased eosinophil cell number ( J:129215 )

• decreased number of circulating eosinophils

decreased monocyte cell number ( J:129215 )

• decreased number of circulating monocytes

abnormal lymphocyte morphology ( J:129215 )

• a number of lymphocytes spontaneously form rosettes with autologous erythrocytes in two thirds of the mice

decreased lymphocyte cell number ( J:129215 )

• lower lymphocyte density

abnormal microglial cell morphology ( J:143173 , J:165019 )

• increased cell size starting at day 100 (J:143173)

• increased granularity starting at day 100 (J:143173)

• large vacuoles in microglial cell cytoplasm in the cervical and lumbar spinal cord (J:165019)

microgliosis ( J:110437 , J:143173 , J:146652 , J:165019 )

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

• microglia (CD11b+ CD45lo) population expanded 1.65-fold by day 135 in spinal cords (J:143173)

• 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 (J:146652)

• first noted at 6 weeks (J:146652)

• some microglial cells occupy areas where formerly occupied by astrocytes or oligodendrocytes in the cervical and lumbar spinal cord (J:165019)

abnormal spleen morphology ( J:138237 )

• diminished follicular architecture with a greater number of follicles at end stage

small spleen ( J:138237 )

• reduced spleen size at end stage (20-22 weeks of age)

decreased spleen weight ( J:138237 )

• reduced spleen weight (45%) at 19 weeks of age

abnormal splenic cell ratio ( J:138237 )

• decreased levels of CD45RA+ (naive) T cells

• increased levels of CD45RO+ (memory) T cells

abnormal splenocyte morphology ( J:138237 )

• increased annexin-V associated apoptosis and necrosis of lymphocytes at pre-symptomatic stage (14 weeks of age)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
amyotrophic lateral sclerosis type 1		DOID:0060193	OMIM:105400	J:133155 , J:143173 , J:146652 , J:212250