Phenotypes associated with this allele

• Allele Symbol: Tg(Prnp-SNCA*A53T)AAub
• Allele Name: transgene insertion A, Georg Auburger
• Allele ID: MGI:3723258
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cx1	Pink1^tm1.1Wrst/Pink1^tm1.1Wrst Tg(Prnp-SNCA*A53T)AAub/?	involves: 129S2/SvPas * C57BL/6J * FVB/N	MGI:6113412
cx2	Snca^tm1Nbm/Snca^tm1Nbm Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub	involves: 129S6/SvEvTac * FVB/N	MGI:3723312
cx3	Pink1^tm1Aub/Pink1^tm1Aub Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub	involves: 129S/SvEv * FVB/N	MGI:5604250
tg4	Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub	involves: 129S6/SvEvTac * FVB/N	MGI:3723310
tg5	Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub	involves: FVB/N	MGI:3723272
tg6	Tg(Prnp-SNCA*A53T)AAub/?	involves: FVB/N	MGI:5639272

Genotype
MGI:6113412

cx1

• Allelic Composition: Pink1^tm1.1Wrst/Pink1^tm1.1Wrst; Tg(Prnp-SNCA*A53T)AAub/?
• Genetic Background: involves: 129S2/SvPas * C57BL/6J * FVB/N

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

mortality/aging

premature death ( J:242309 )

• mice show a reduced life span

nervous system

abnormal dopaminergic neuron morphology ( J:242309 )

• nucleolar integrity is disrupted in dopaminergic neurons, with the percentage of TH+ dopaminergic neurons containing one nucleolus being lower in the substantia nigra and ventral tagmental area and an increase in the percentage of dopaminergic neurons showing no nucleolar staining

• number of dopaminergic neurons containing 2 or 3 nucleoli is higher

cellular

abnormal nucleolus morphology ( J:242309 )

• nucleolar integrity is disrupted in dopaminergic neurons, with the percentage of TH+ dopaminergic neurons containing one nucleolus being lower in the substantia nigra and ventral tagmental area and an increase in the percentage of dopaminergic neurons showing no nucleolar staining

• number of dopaminergic neurons containing 2 or 3 nucleoli is higher

abnormal cell physiology ( J:242309 )

• nucleolar activity is altered with downregulation in a subset of dopaminergic neurons while upregulation of rRNA synthesis is seen in another group of dopaminergic neurons suggesting initial compensatory mechanisms

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:242309

Genotype
MGI:3723312

cx2

• Allelic Composition: Snca^tm1Nbm/Snca^tm1Nbm; Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub
• Genetic Background: involves: 129S6/SvEvTac * FVB/N

mortality/aging

premature death ( J:124976 )

• no mutants survive past 23 months, whereas controls show 60% survival at 24 months of age; mortality is significantly higher than in SCNA^tm1Nsb 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

slow postnatal weight gain ( J:124976 )

• 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

weight loss ( J:124976 )

• 12-20% loss in body weight is observed ~2 weeks prior to onset of motor dysfunction in limbs

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:124976 )

• dysfunction in a single hindlimb is usually the first pathological sign

abnormal reflex ( J:124976 )

• when suspended by the tail, mice do not show limb clasping, but limbs hang limply, and never are splayed as in wild-type

weakness ( J:124976 )

abnormal posture ( J:124976 )

• eventually, animals cannot support themselves and lay on their sides

abnormal gait ( J:124976 )

• in affected animals, knuckle-walking progressing to dragging of the hindlimbs is observed

short stride length ( J:124976 )

• at 17-18 months, mice show a shorter fore- and hindstride length

nervous system

gliosis ( J:124976 )

• marked gliosis is seen in affected mice, with none in controls

abnormal axon morphology ( J:124976 )

• sciatic nerves of affected animals show much greater damage and loss of axonal material

neuronal intranuclear inclusions ( J:124976 )

• presence of inclusion bodies (structureless smooth areas) is detected in spinal cords of some affected animals

abnormal spinal nerve morphology ( J:124976 )

• axons in dorsal and ventral roots in the spinal cord show heavy expression of SNCA compared to wild-type

abnormal ventral spinal root morphology ( J:124976 )

• in 19 month-old mice, more ventral root axons display empty sheaths or diminished, compressed contents than wild-type ventral roots

abnormal spinal cord ventral horn morphology ( J:124976 )

• 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

axon degeneration ( J:124976 )

• some degenerating axons are observed within intact myelin sheaths in the spinal cord

endocrine/exocrine glands

abnormal male preputial gland morphology ( J:124976 )

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

skeleton

kyphosis ( J:124976 )

reproductive system

abnormal male preputial gland morphology ( J:124976 )

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

renal/urinary system

abnormal male preputial gland morphology ( J:124976 )

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

integument

abnormal male preputial gland morphology ( J:124976 )

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

Genotype
MGI:5604250

cx3

• Allelic Composition: Pink1^tm1Aub/Pink1^tm1Aub; Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub
• Genetic Background: involves: 129S/SvEv * FVB/N

behavior/neurological

abnormal locomotor behavior ( J:214065 )

decreased vertical activity ( J:214065 )

• reduction in vertical activity by 3 months of age

decreased locomotor activity ( J:214065 )

• reductions in horizontal activity by 3 months of age

hindlimb paralysis ( J:214065 )

• 25% of mice exhibit progressive hindlimb paralysis at ages greater than 1 year

paresis ( J:214065 )

• 16/60 mice older than one year exhibit flaccid paresis of the hindlimbs, progressing to full paraplegia

decreased stereotypic behavior ( J:214065 )

• reductions in stereotype movement counts by 3 months of age

mortality/aging

premature death ( J:214065 )

• 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

abnormal motor neuron morphology ( J:214065 )

• protein aggregates with pSer129-SNCA, P62, and ubiquitin immunoreactivity appears as granular and thread-like in neuronal cytoplasm of neurons with extensions along neurites

abnormal neurite morphology ( J:214065 )

• some neurites exhibit corkscrew morphology

alpha-synuclein inclusion body ( J:214065 )

• 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

neurodegeneration ( J:214065 )

skeleton

kyphosis ( J:214065 )

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease		DOID:14330	OMIM:PS168600	J:214065

Genotype
MGI:3723310

tg4

• Allelic Composition: Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub
• Genetic Background: involves: 129S6/SvEvTac * FVB/N

mortality/aging

premature death ( J:124976 )

• mice show increased survival relative to SNCA-null transgenic animals, but survival is reduced relative to wild-type or SNCA-null mice

Genotype
MGI:3723272

tg5

• Allelic Composition: Tg(Prnp-SNCA*A53T)AAub/Tg(Prnp-SNCA*A53T)AAub
• Genetic Background: involves: FVB/N

behavior/neurological

impaired coordination ( J:86222 )

• 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

decreased grip strength ( J:86222 )

• grip strength of forelimbs is significantly impaired (67 ponds) relative to controls (125 ponds)

weakness ( J:86222 )

• grip strength of forelimbs is significantly impaired (67 ponds) relative to controls (125 ponds)

short stride length ( J:86222 )

• step length of transgenic animals is reduced relative to wild-type (1.9 cm vs 2.25 cm in wild-type)

decreased vertical activity ( J:86222 )

• 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

nervous system

abnormal neurite morphology ( J:86222 )

• signs such as ballooning and kinky, tortuous, or corkscrew shapes of neurites are observed

alpha-synuclein inclusion body ( J:185489 )

• 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

neurodegeneration ( J:86222 )

• 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

absent long-term depression ( J:181820 )

• 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

premature death ( J:214065 )

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

digestive/alimentary system

abnormal defecation ( J:185489 )

• 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

abnormal digestion ( J:185489 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease 1		DOID:0060367	OMIM:168601	J:181820 , J:185489

Genotype
MGI:5639272

tg6

• Allelic Composition: Tg(Prnp-SNCA*A53T)AAub/?
• Genetic Background: involves: FVB/N

nervous system

abnormal nervous system electrophysiology ( J:216589 )

♂ • 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

abnormal neuron physiology ( J:216589 )

♂ • 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

abnormal channel response ( J:216589 )

♂ • 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		DO ID	OMIM ID(s)	Ref(s)
Parkinson's disease 1		DOID:0060367	OMIM:168601	J:216589