Mouse Genome Informatics
cx1
    Pink1tm1Aub/Pink1tm1Aub
Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub

involves: 129S/SvEv * FVB/N
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
behavior/neurological
• reduction in vertical activity by 3 months of age
• reductions in horizontal activity by 3 months of age
• 25% of mice exhibit progressive hindlimb paralysis at ages greater than 1 year
• 16/60 mice older than one year exhibit flaccid paresis of the hindlimbs, progressing to full paraplegia
• reductions in stereotype movement counts by 3 months of age

mortality/aging
• late onset increase in mortality rate at 450 days as compared to wild-type controls
• some mice develop a lethal motor deficit at greater than one year

nervous system
• protein aggregates with pSer129-SNCA, P62, and ubiquitin immunoreactivity appears as granular and thread-like in neuronal cytoplasm of neurons with extensions along neurites
• some neurites exhibit corkscrew morphology
• protein aggregates with pSer129-SNCA, P62 and ubiquitin immunoreactivity are observed in grey matter of lumbar spinal cord of paralyzed animals aged to 15-17 months
• aggregate pathology is milder in thoracic and cervical spinal cord
• immunoreactivity appears as granular and thread-like in neuronal cytoplasm of neurons with extensions along neurites
• protein aggregates are observed in non-paralyzed animals, but with little neurite pathology
• discrete lesions are found in motor cortex, but not striatum of paralyzed mice
• minimal lesions are found in ventral tegmental area of non-paralytic mice
• aggregate formation is found in non-dopaminergic neurons (NeuN-positive)
• no aggregate formation is found in dopaminergic neurons

skeleton
• 3/60 mice older than one year exhibit kyphosis, falls and rigidity


Mouse Genome Informatics
cx2
    Sncatm1Nbm/Sncatm1Nbm
Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub

involves: 129S6/SvEvTac * FVB/N
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• no mutants survive past 23 months, whereas controls show 60% survival at 24 months of age; mortality is significantly higher than in SCNAtm1Nsb homozygotes or Tg(Prnp-SNCA*A53T)BAub homozygotes
• major cause of death is a late onset neuronopathy, with onset from 16 to 23 months

growth/size/body
• mice weigh same as controls at 12-13 months of age, but differ at 17-18 months (42.6 gm vs 48.5 g wt) and reach a weight plateau at this age whereas controls continue to gain weight to 2 years of age
• 12-20% loss in body weight is observed ~2 weeks prior to onset of motor dysfunction in limbs

behavior/neurological
• dysfunction in a single hindlimb is usually the first pathological sign
• when suspended by the tail, mice do not show limb clasping, but limbs hang limply, and never are splayed as in wild-type
• eventually, animals cannot support themselves and lay on their sides
• in affected animals, knuckle-walking progressing to dragging of the hindlimbs is observed
• at 17-18 months, mice show a shorter fore- and hindstride length

nervous system
• marked gliosis is seen in affected mice, with none in controls
• sciatic nerves of affected animals show much greater damage and loss of axonal material
• presence of inclusion bodies (structureless smooth areas) is detected in spinal cords of some affected animals
• axons in dorsal and ventral roots in the spinal cord show heavy expression of SNCA compared to wild-type
• in 19 month-old mice, more ventral root axons display empty sheaths or diminished, compressed contents than wild-type ventral roots
• perinuclear lipid deposits are observed in the cytoplasm of some motor neurons
• increased lysosomal activity is detected in spinal cord
• in thoracic ventral horns of affected animals, accumulation of Lamp1-positive structures is seen in many motor neuron cell bodies, along with occasional large vacuoles
• some degenerating axons are observed within intact myelin sheaths in the spinal cord

endocrine/exocrine glands
• many animals' deaths are due to abscessed preputial gland cysts

skeleton

reproductive system
• many animals' deaths are due to abscessed preputial gland cysts

renal/urinary system
• many animals' deaths are due to abscessed preputial gland cysts

integument
• many animals' deaths are due to abscessed preputial gland cysts


Mouse Genome Informatics
tg3
    Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub
involves: 129S6/SvEvTac * FVB/N
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• mice show increased survival relative to SNCA-null transgenic animals, but survival is reduced relative to wild-type or SNCA-null mice


Mouse Genome Informatics
tg4
    Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub
involves: FVB/N
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
behavior/neurological
• up to 4 months of age, mutants perform better than controls on the accelerating rotating rod, but beyond 4 months, display progressive difficulties maintaining balance
• grip strength of forelimbs is significantly impaired (67 ponds) relative to controls (125 ponds)
• grip strength of forelimbs is significantly impaired (67 ponds) relative to controls (125 ponds)
• progressive reduction in rearing behavior is observed in animals at 6, 18, and 24 months of age, with notably decreased activity apparent at 3 months of age
• step length of transgenic animals is reduced relative to wild-type (1.9 cm vs 2.25 cm in wild-type)

nervous system
• signs such as ballooning and kinky, tortuous, or corkscrew shapes of neurites are observed
• accumulation of human alpha-synuclein is seen in nerve terminals and cell bodies in the dorsal motor nucleus of the vagus nerve and in axon terminals innervating the gastric myenteric plexus, although accumulation is diffuse and does not show Lewy body-like appearance
• signs such as ballooning and kinky, tortuous, or corkscrew shapes of neurites are observed
• at 7 months of age, such abnormalities are seen only occasionally in the neocortex and hippocampus, but are frequently seen in a dense network of neurites in the olfactory bulb
• corticostriatal long-term depression (LTD) is absent in old, but not young, mutants
• dopamine does not restore LTD in old mice, however, zaprinast, an inhibitor of phosphodiesterases, restores LTD
• mice, however, do not exhibit age-related differences in striatal excitability

mortality/aging
• increased mortality rate in the first 180 days as compared to wild-type controls

digestive/alimentary system
• stool frequency is normal at 2 months of age but is 15%, 21%, and 40% lower at 9, 15, and 19 months of age, respectively
• total wet weight of stool and stool water content are lower in 19 month old mice compared to controls, however stool dry weight is no different and food intake and body weight are similar to controls
• mice show a decline in gastric emptying with age, with twice as much residual food remaining in the stomachs of 20 month old mutants as in controls

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease 1, Autosomal Dominant; PARK1 168601 J:181820 , J:185489


Mouse Genome Informatics
tg5
    Tg(Prnp-SNCA*A53T)AAub/?
involves: FVB/N
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
nervous system
• middle-aged (7-8 months) dopaminergic substantia nigra neurons show an approximate 100% increase in mean firing rates, prolonged action potential repolarization, and more prominent pacemaking patterns
• however, electrical activity of dopaminergic ventral tegmental area neurons is not altered
• dopaminergic substantia nigra neurons from young (3-4 months) adults already show faster in vivo firing frequencies compared to controls, with mean firing frequencies about 50% higher, however, differences in action potential repolarization are not yet apparent at 3-4 months of age
• the regularity of firing is lower in 3 month old dopaminergic substantia nigra neurons
• middle-aged (7-8 months) dopaminergic substantia nigra neurons show an approximate 100% increase in mean firing rates, prolonged action potential repolarization, and more prominent pacemaking patterns, with faster firing frequencies seen already at 3-4 months of age
• approximate 40% reduction of maximal A-type Kv4.3 potassium conductances in dopaminergic substantia nigra neurons of middle-aged mice
• intracellular dialysis of the reducing agent glutathione rescues the A-type K channel dysfunction

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease 1, Autosomal Dominant; PARK1 168601 J:216589