Mouse Genome Informatics
hm1
    Sncatm1Rosl/Sncatm1Rosl
B6.129X1-Sncatm1Rosl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• at P2, homozygotes display normal numbers of sensory neurons in trigeminal ganglia and L6 lumbar dorsal root ganglia relative to wild-type controls (J:86439)
• homozygotes exhibit normal morphology and numbers of myelinated A-fibers and unmyelinated C-fibers in adult saphenous nerves relative to wild-type controls (J:86439)
• in culture, neurons from P2 peripheral (trigeminal and superior cervical) ganglia of mutant mice display the same survival rate as wild-type neurons in the presence of nerve growth factor and, as expected, fail to survive in its absence (J:86439)
• homozygotes display no gross abnormalities of the nervous system relative to wild-type controls (J:92213)
• no significant differences in dopamine or its metabolite (DOPAC, 5-HIAA and HVA) levels are noted in the striatum at 9 months of age (J:92213)
• homozygotes display resistance of SNpc dopaminergic neurons to MPTP neurotoxicity
• adult homozygotes show a ~20% reduction in the number of tyrosine hydroxylase (TH)-positive dopaminergic neurons in substantia nigra pars compacta (SNpc) but not in ventral tegmental area (VTA) relative to wild-type controls, similar to that observed in adult Sncgtm1Vlb homozygotes
• however, no significant decrease in the number of TH-positive dopaminergic neurons is observed in SNpc after methyl-phenyl-tetrahydropyridine (MPTP) treatment relative to controls

homeostasis/metabolism
• homozygotes display resistance of SNpc dopaminergic neurons to MPTP neurotoxicity

behavior/neurological
N
• homozygotes are behaviorally normal and show no detectable motor dysfunction in either constant speed or accelerating rotarod tests (J:92213)

cellular
• homozygotes display resistance of SNpc dopaminergic neurons to MPTP neurotoxicity


Mouse Genome Informatics
hm2
    Sncatm1Rosl/Sncatm1Rosl
involves: 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mice do not exhibit as much dopamine neuron loss following injection of LPS into the substantia nigra as similarly treated wild-type mice


Mouse Genome Informatics
hm3
    Sncatm1Rosl/Sncatm1Rosl
involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• dopamine content is reduced by 18% in the striatum, however, dopamine content in the ventral midbrain and nucleus accumbens is similar to wild-type
• when exposed to paired electrical stimuli, striatal brain slices (containing dopamine terminals) from homozygous mice exhibit a faster dopamine release recovery as compared to wild-type
• dopamine discharge and reuptake in response to a single electrical pulse or a train of pulses is comparable to wild-type

behavior/neurological
• homozygous mice exhibit an attenuated locomotor response after administration of amphetamine as compared to wild-type
• in the absence of amphetamine, locomotor activity in the open field test is comparable to wild-type

homeostasis/metabolism
• dopamine content is reduced by 18% in the striatum, however, dopamine content in the ventral midbrain and nucleus accumbens is similar to wild-type

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease 1, Autosomal Dominant; PARK1 168601 J:60151


Mouse Genome Informatics
cx4
    Sncatm1Rosl/Sncatm1Rosl
Sncgtm1Vlb/Sncgtm1Vlb

B6.129-Sncatm1Rosl Sncgtm1Vlb
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• double homozygotes are viable, fertile and display no gross abnormalities of the nervous system (J:92213)
• no significant differences in dopamine or its metabolite (DOPAC, 5-HIAA and HVA) levels are noted in the striatum at 9 months of age (J:92213)
• similar to single homozygotes, double homozygotes display resistance of SNpc dopaminergic neurons to MPTP neurotoxicity
• adult double homozygotes show a ~20% reduction in the number of tyrosine hydroxylase (TH)-positive dopaminergic neurons in substantia nigra pars compacta (SNpc) but not in ventral tegmental area (VTA) relative to wild-type controls, similar to that observed in adult single homozygotes
• however, no significant decrease in the number of TH-positive dopaminergic neurons is observed in SNpc after methyl-phenyl-tetrahydropyridine (MPTP) treatment relative to controls

homeostasis/metabolism
• similar to single homozygotes, double homozygotes display resistance of SNpc dopaminergic neurons to MPTP neurotoxicity

behavior/neurological
N
• double homozygotes are behaviorally normal and show no detectable motor dysfunction in either constant speed or accelerating rotarod tests (J:92213)

cellular
• similar to single homozygotes, double homozygotes display resistance of SNpc dopaminergic neurons to MPTP neurotoxicity


Mouse Genome Informatics
cx5
    Sncatm1Rosl/Sncatm1Rosl
Tg(SNCA*A30P)#Rwm/0

B6.Cg-Sncatm1Rosl Tg(SNCA*A30P)#Rwm
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• aged mutants do not exhibit catecholaminergic neuron loss or alpha-synuclein neuropathology and show normal novelty-induced activity, forepaw stride length, activity on the accelerating rotarod, anxiety, immobility times in the tail suspension test, circadian rhythms, and spontaneous alternation in the T-maze (J:201961)
• mutants are more active in wheel running during the dark phase, however activity in locomotor cages is normal

homeostasis/metabolism
• electrically evoked release of dopamine is reduced in the caudate putamen, but not in the nucleus accumbens compared to single homozygous Sncatm1Rosl mutants, and show normal norepinephrine release in the stria terminalis

nervous system
• mutants are sensitive to the dopaminergic neurotoxin, MPTP, showing nigral and striatal damage, unlike single homozygous Sncatm1Rosl mutants which show resistance
• electrically evoked release of dopamine is reduced in the caudate putamen, but not in the nucleus accumbens compared to single homozygous Sncatm1Rosl mutants, and show normal norepinephrine release in the stria terminalis

digestive/alimentary system
N
• mutants appear to have normal gastrointestinal function as shown by normal stool water content, stool dry weight and stool frequency (J:201961)

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease 1, Autosomal Dominant; PARK1 168601 J:201961


Mouse Genome Informatics
cx6
    Sncatm1Rosl/Sncatm1Rosl
Tg(SNCA)OVXRwm/0

B6.Cg-Tg(SNCA)OVXRwm Sncatm1Rosl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• 18 month old mutants show a reduced latency to fall on the rotarod test and are impaired on the multiple static rods test
• however, no differences in the latency to fall in the inverted screen test is seen
• reduction in forepaw stride length in 18 month old mutants

digestive/alimentary system
• dry stool weight is increased in males but not females, independent of age; however, stool frequency and stool water content are normal, indicating constipation-like phenotype (J:201991)

homeostasis/metabolism
• net dopamine content is unchanged in caudate putamen or nucleus accumbens at 3-4 and 12 months of age, however at 18 months of age, dopamine content is greater in the caudate putamen

nervous system
• net dopamine content is unchanged in caudate putamen or nucleus accumbens at 3-4 and 12 months of age, however at 18 months of age, dopamine content is greater in the caudate putamen
• vesicles in dopamine axons of the dorsal striatum are more clustered than in controls at 3 months of age; the frequency distribution of intervesicle distance is reduced and vesicles are 3 times less dispersed
• 18 month old mutants exhibit loss of substantia nigra pars compacta dopamine neurons
• 18 month old mutants exhibit loss of substantia nigra pars compacta dopamine neurons
• however, aggregation of alpha-synuclein is not seen in the substantia nigra pars compacta or striatum
• substantia nigra pars compacta dopamine neurons exhibit age-dependent reductions (almost 30%) in firing rates in vivo
• in the dorsal striatum, mean peak extracellular concentrations of dopamine evoked by single electrical pulses across distributed recording sites are on average about 30% lower than in controls; this reduced release is seen from a young age of 3-4 months before the loss of dopamine neurons and persists throughout their lifespan
• greatest deficits in dopamine release are seen in the dorsal and lateral striatum
• the dopamine release deficit persists in the presence of nicotinic receptor blockade by dihydro-beta-erythroidine
• dopamine uptake kinetics are normal and norepinephrine and 5-hydroxytryptamine axonal release are normal


Mouse Genome Informatics
cx7
    Sncatm1Rosl/Sncatm1Rosl
Tg(Prnp-SNCA*A53T)83Vle/Tg(Prnp-SNCA*A53T)83Vle

involves: 129X1/SvJ * C3H * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• following injection of LPS into the substantia nigra
• following injection of LPS into the substantia nigra, mice exhibit an increased loss of dopaminergic neurons that is associated with insoluble and aggregated SNCA compared to in Sncatm1Rosl Tg(Prnp-SNCA)7Vle and Sncatm1Rosl homozygotes
• however, loss of dopamine neurons is not due to an abnormal inflammatory response following injection of LPS into the substantia nigra

immune system
• following injection of LPS into the substantia nigra, mice exhibit an increased loss of dopaminergic neurons compared to in Sncatm1Rosl Tg(Prnp-SNCA)7Vle and Sncatm1Rosl homozygotes


Mouse Genome Informatics
cx8
    Sncatm1Rosl/Sncatm1Rosl
Tg(Prnp-SNCA)7Vle/Tg(Prnp-SNCA)7Vle

involves: 129X1/SvJ * C3H * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• following injection of LPS into the substantia nigra
• following injection of LPS into the substantia nigra, mice exhibit an increased loss of dopaminergic neurons that is associated with insoluble and aggregated SNCA compared to in Sncatm1Rosl homozygotes
• following culture with LPS, dopaminergic neurons loss is increased compared to in cultures from Sncatm1Rosl homozygotes
• loss of dopamine neurons following injection of LPS into the substantia nigra is mediated by microglial-derived nitric oxide and superoxideloss of dopamine neurons following injection of LPS into the substantia nigra is mediated by microglial-derived nitric oxide and superoxide
• however, loss of dopamine neurons is not due to an abnormal inflammatory response following injection of LPS into the substantia nigra

immune system
• following injection of LPS into the substantia nigra, mice exhibit a decreased loss of dopaminergic neurons compared to in Sncatm1Rosl Tg(Prnp-SNCA*A53T)83Vle homozygotes but increased relative to in Sncatm1Rosl homozygotes