Mouse Genome Informatics
cn1
    Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+
Park2tm1Roo/Park2tm1Roo
Slc6a3tm1(cre)Lrsn/Slc6a3+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129S2/SvPas * 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
• YFP+ neurons exhibit one or more grossly enlarged, rounded mitochondria in the perinuclear region of the soma and in proximal segment of dendrites with some cells containing fragmented mitochondria and small, spherical mitochondrial clustered around the nucleus
• YFP+ neurons exhibit a progressive reduction in distal axonal mitochondrial numbers compared with control cells
• however, mitochondria in the distal dopamine axons are morphologically spared
• neurons exhibit less intense staining with a retrograde tracer (fluorogold) suggesting impaired retrograde transport and/or uptake of the tracer compared with control cells


Mouse Genome Informatics
cn2
    Slc6a3tm1(cre)Lrsn/Slc6a3+
Sncatm1Nbm/Sncatm1Nbm
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• triple mutants show same phenotype as Tfamtm1Lrsn, Slc6a3tm1(cre)Lrsn mice; neuronal inclusions remain indicating that additional lack of Snca is not required for develoment of the Parkonsonian phenotype


Mouse Genome Informatics
cn3
    Nr4a2tm1.1Ich/Nr4a2tm1.1Ich
Slc6a3tm1(cre)Lrsn/Slc6a3tm1(cre)Lrsn

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice do not survive beyond 3 weeks
• however, leaving pups with mothers improves perinatal survival beyond 3 weeks

nervous system
• at P1, striatal dopamine levels are decreased to 14% of wild-type
• at P14, the ratio of homovanillic acid (HVA) to dopamine is increased indicating increased dopamine turnover compared to in wild-type mice
• at P60, striatal dopamine levels are almost completely lost unlike in wild-type mice
• at P60, dopamine levels are more severely decreased in the caudate putamen compared to in the nucleus accumbens
• expression of midbrain dopamine neuron markers is lost compared to in wild-type mice
• mice exhibit a rapid loss of substantia nigra pars compacta cell bodies with only scattered ventral tegmental area neurons remaining compared with wild-type mice

behavior/neurological
• at 4 and 14 months
• L-DOPA-treated mice exhibit hyperactivity unlike similarly treated wild-type mice
• L-DOPA-treated mice exhibit repetitive behaviors (including repetitive gnawing, excessive grooming, and self-injury) unlike similarly treated wild-type mice

homeostasis/metabolism
• at P1, striatal dopamine levels are decreased to 14% of wild-type
• at P14, the ratio of homovanillic acid (HVA) to dopamine is increased indicating increased dopamine turnover compared to in wild-type mice
• at P60, striatal dopamine levels are almost completely lost unlike in wild-type mice
• at P60, dopamine levels are more severely decreased in the caudate putamen compared to in the nucleus accumbens
• serotonin levels in the caudate putamen and nucleus accumbens are increased compared to in wild-type mice
• L-DOPA-treated mice exhibit hyperactivity and repetitive behaviors unlike similarly treated wild-type mice

growth/size
• at 2 months, mice left with their mothers after weaning are 40% smaller than wild-type mice


Mouse Genome Informatics
cn4
    Mfn1tm1.1Arte/Mfn1tm1.1Arte
Slc6a3tm1(cre)Lrsn/Slc6a3+

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• viable with normal locomotor activity and body weight


Mouse Genome Informatics
cn5
    Mfn2tm1.1Arte/Mfn2tm1.1Arte
Slc6a3tm1(cre)Lrsn/Slc6a3+

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• die before 7 weeks of age with a median survival of 5.8 weeks
• life span can be increased to 11-12 weeks of age when provided with moist food on the cage floor

nervous system
• severe reduction in the striatum at 5 weeks of age
• also reduced in the substantia nigra pars compacta
• pathological alterations (irregular margins and elongated nuclei) of the somata of the substantia nigra pars compacta are seen at 5 weeks of age
• profound lack of dopaminergic neuron innervation in the striatum
• severe respiratory chain deficiency in mitochondria in dopaminergic neurons

growth/size
• at 5 weeks of age
• continue to lose weight even when provided with moist food on the cage floor

behavior/neurological
• total distance traveled is significantly increased in an open field test
• however, locomotion as assessed by horizontal beam breaks is similar to controls
• decreased rearing activity in an open field test
• become severely hypokinetic with age

cellular
• severe respiratory chain deficiency in mitochondria in dopaminergic neurons

homeostasis/metabolism
• severe reduction in the striatum at 5 weeks of age
• also reduced in the substantia nigra pars compacta
• in the striatum


Mouse Genome Informatics
cn6
    Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+
Mfn2tm1.1Arte/Mfn2tm1.1Arte
Slc6a3tm1(cre)Lrsn/Slc6a3+

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• profound reduction in the number of labeled mitochondria in the dorsal striatum
• mitochondria are spherical and enlarged with disorganized cristae

cellular
• mitochondria in dopaminergic neurons are spherical and enlarged with disorganized cristae
• profound reduction in the number of labeled mitochondria in the dorsal striatum
• mitochondria in dopaminergic neurons are spherical and enlarged with disorganized cristae


Mouse Genome Informatics
cn7
    Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+
Slc6a3tm1(cre)Lrsn/Slc6a3+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Mitochondria abnormalities in Tfamtm1Lrsn/Tfamtm1Lrsn Slc6a3tm1(cre)Lrsn/Slc6a3+ Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+ neurons

nervous system
• YFP+ neurons exhibit one or more grossly enlarged, rounded mitochondria in the perinuclear region of the soma and in proximal segment of dendrites with some cells containing fragmented mitochondria and small, spherical mitochondrial clustered around the nucleus
• YFP+ neurons exhibit a progressive reduction in distal axonal mitochondrial numbers compared with control cells

cellular
• smaller mitochondrial and the largest aggregates in a rare number of neurons exhibit reduced import competence compared with mitochondria in control cells

behavior/neurological
• impaired from 20 weeks of age

growth/size
• from 20 weeks of age

muscle
• rigidity from 20 weeks of age


Mouse Genome Informatics
cn8
    Slc6a3tm1(cre)Lrsn/Slc6a3+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants have to be terminated at ~45 weeks due to poor general condition

behavior/neurological
• mice aged 14-15 weeks display decreased exploratory activity
• progressive Parkinsonian symptoms are observed, with tremor observed at 20 weeks of age
• apparent limb rigidity is observed at 20 weeks of age

nervous system
• neuron loss results in loss of dopamine in the nigrostriatal system in 20-week old mice
• there are markedly increased ratios of dopamine metabolites to dopamine in the striatum at 20 weeks
• majority of neurons contain small cytoplasmic aggregates, detected at 6 weeks through 43 weeks
• inclusions are present in most dopaminergic midbrain neurons and the mean size increased as the neurodegeneration progressed
• large, partially electron-dense bodies located in dendritic structures close to neuronal somata are observed at 11 weeks; some of these bodies have an amorphous content with a diffuse lining, while others display tubular formations and have distinct double layer membranes which are ultrastructurally typical of mitochondrial membranes
• dopaminergic (DA) neuron loss is observed in the dorsolateral striatum at 12 weeks of age, progressing to involve most of the dorsal and ventral striatum with age
• tyrosine hydroxylase-expressing midbrain neurons show a slow progressive cell loss, which is more marked and starts sooner in the substantia nigra compared to the ventral tegmental area

muscle
• twitching is observed at 20 weeks of age

homeostasis/metabolism
• neuron loss results in loss of dopamine in the nigrostriatal system in 20-week old mice
• there are markedly increased ratios of dopamine metabolites to dopamine in the striatum at 20 weeks

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease, Mitochondrial 556500 J:119515