Analysis Tools
mortality/aging
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• all mice die or are euthanized by P40
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growth/size/body
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• mice fail to gain weight past P18
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• mice develop normally until P18 but fail to thrive and subsequently are smaller than wild-type controls
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behavior/neurological
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• loss of balance and rolling after ~P25
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• uncoordinated movement first seen at ~P25
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• mice exhibit significantly reduced grip strength at P22-P26 relative to wild-type controls
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• in the weanling observation test, weanling pups exhibit significantly less total activity from P19-P21 relative to wild-type controls
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• lack of response to stimuli by P40
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muscle
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• in the hind limb suspension test, neonates show reduced muscle strength performance, with a consistently shorter hang time and decreased number of pull attempts starting at P7 and continuing to P10
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immune system
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• mice are lymphopenic
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cellular
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• mice exhibit accumulation of swollen, structurally abnormal mitochondria with loss of inner membrane architecture in cerebellar granule cells
• mitochondrial structural defects precede cerebellar cell death and are accompanied by defective processing of OPA1, a key molecule for mitochondrial fusion and cristae remodeling, leading to depletion of the L-isoform
• abnormal OPA1 processing is brain-specific and detected as early as P9
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• EM revealed that cerebellar granule cells show abnormalities in the mitochondrial inner membrane architecture but not in the outer membrane organization
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• fragmentation of the mitochondrial cristae in cerebellar granule cells
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• increased numbers of swollen mitochondria in the cerebellar granule layer at both P20 and P32 relative to wild-type controls
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• mice show a significant increase in the number of TUNEL+ cells in discrete brain regions, i.e. striatum, cerebellum and entorhinal cortex, at P30 relative to wild-type controls
• cell death in the striatum and cerebellum is detectable by P25 and progressively worsens over time
• dying cells in the entorhinal cortex are seen at P30 but not at P25
• whereas cell death is widespread in the striatum, cerebellar cell death appears to be localized in the granule cell layer with a prominent amount of TUNEL+ cells
• mitochondrial defects precede cell death in the cerebellum
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• at P25, Complex I and Complex II enzyme levels are reduced in the cerebellar granule cell layer and in the striatum, but not in the cerebral cortex, relative to wild-type controls, suggesting that electron transport chain function is impaired
• reduction in the levels of respiratory enzymes is confined to the regions that undergo cell death
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nervous system
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• mice show a significant increase in the number of TUNEL+ cells in discrete brain regions, i.e. striatum, cerebellum and entorhinal cortex, at P30 relative to wild-type controls
• cell death in the striatum and cerebellum is detectable by P25 and progressively worsens over time
• dying cells in the entorhinal cortex are seen at P30 but not at P25
• whereas cell death is widespread in the striatum, cerebellar cell death appears to be localized in the granule cell layer with a prominent amount of TUNEL+ cells
• mitochondrial defects precede cell death in the cerebellum
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• at P20 (i.e. prior to the onset of cerebellar cell death), cerebellar granule cells show increased incidence of abnormally structured mitochondria, including mitochondrial swelling, vesiculation, and fragmentation of the cristae
• despite increased cerebellar cell death, P30-P35 cerebella appear grossly unaffected, with no signs of demyelination and normal Purkinje cell organization, neuronal populations and granule cell layer morphology relative to wild-type controls
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hematopoietic system
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• mice are lymphopenic
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endocrine/exocrine glands
