Phenotypes Associated with This Genotype

Genotype
MGI:6458731

• Allelic Composition: Ap5z1^{tm1(KOMP)Wtsi}/Ap5z1^{tm1(KOMP)Wtsi}
• Genetic Background: involves: 129 * C57BL/6N
• Cell Lines: EPD0587_5_A05

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

behavior/neurological

behavior/neurological phenotype ( J:283611 )

N • mice exhibit no learning or memory deficits in the Morris water maze paradigm at 6 months of age

abnormal gait ( J:283611 )

• mice develop mild progressive gait abnormalities; the foot-base-angle at toe-off position is significantly reduced at 20 months (55 degrees versus 75 degrees in wild-type controls), but not at 12 or 16 months of age

nervous system

abnormal hippocampus pyramidal cell morphology ( J:283611 )

• accumulation of autofluorescent material in pyramidal neurons of layer V of the motor cortex at 8 months of age

abnormal Purkinje cell morphology ( J:283611 )

• accumulation of autofluorescent material in Purkinje neurons at 8 months of age, with larger clusters of membrane-associated electron-dense deposits of abnormal shape observed ultrastructurally at 20 months of age

• strong activation of astrocytes in the Purkinje cell layer at 20 months of age

• however, numbers of Purkinje cell bodies and Purkinje cell mitochondria remain normal

abnormal Purkinje cell axon morphology ( J:283611 )

• Lamp1-positive axonal swellings in Purkinje cells at 20 months of age

abnormal cerebellar granule layer morphology ( J:283611 )

• strong activation of astrocytes in the granular cell layer of the cerebellum at 20 months of age

• however, the molecular layer is normal

astrocytosis ( J:283611 )

• strong activation of astrocytes in the granular cell layer of the cerebellum and in the Purkinje cell layer at 20 months of age

abnormal corticospinal tract morphology ( J:283611 )

• large diameter axons are almost absent in the lumbar corticospinal tract at 20 months of age

axon degeneration ( J:283611 )

• mice show a significant reduction of large diameter axons and various signs of axon degeneration, including abnormal membranous material, in the lumbar corticospinal tract at 20 months of age

axonal spheroids ( J:283611 )

• large Lamp1-positive spheroids with a diameter of up to 15 um, resembling lysosomes and autolysosomes, found in the corticospinal tract of the lumbar spinal cord and in the granular layer of the cerebellum at 20 months of age

cellular

abnormal Golgi apparatus morphology ( J:283611 )

• mouse embryonic fibroblasts (MEFs) show a reduction in the relative area of TGN38-positive structures (transGolgi) but not Giantin-positive structures (cisGolgi)

• ultrastructural analysis of Golgi stacks shows an increased number of MEFs with a vesiculated Golgi apparatus

• signals for transGolgi proteins (TGN38 and Glg1) are reduced in Purkinje cells at 20 months, but not at 2 months of age

abnormal Golgi stack morphology ( J:283611 )

• mean size of individual Golgi stacks is significantly decreased in MEFs

impaired autophagy ( J:283611 )

• upon starvation-induced autophagy, MEFs show a significant increase in autophagosome numbers as well as a significant decrease in autolysosome numbers, indicating a block in autophagic flux under stressed conditions

• upon prolonged starvation (8-9 h), MEFs show impaired autophagic lysosome reformation; number of cells with >5 Lamp1-positive tubules longer than 2 um and level of S6K phosphorylation are significantly lower than in similarly treated wild-type cells

• at 2 months of age (i.e. prior to accumulation of autofluorescent material), numbers of autophagosomes and autolysosomes are significantly increased while lysosomal numbers are normal in Purkinje cell bodies

• at 20 months of age, brains show accumulation of autophagic deposits that are positive for both Lamp1 (a lysosomal membrane protein) and the autophagic cargo receptor p62

abnormal lysosome physiology ( J:283611 )

• MEFs show impaired cycling of lysosomes from autolysosomes

abnormal Golgi vesicle transport ( J:283611 )

• analysis of MEFs suggests a trafficking defect from late endosomes to the transGolgi network

homeostasis/metabolism

impaired autophagy ( J:283611 )

• upon starvation-induced autophagy, MEFs show a significant increase in autophagosome numbers as well as a significant decrease in autolysosome numbers, indicating a block in autophagic flux under stressed conditions

• upon prolonged starvation (8-9 h), MEFs show impaired autophagic lysosome reformation; number of cells with >5 Lamp1-positive tubules longer than 2 um and level of S6K phosphorylation are significantly lower than in similarly treated wild-type cells

• at 2 months of age (i.e. prior to accumulation of autofluorescent material), numbers of autophagosomes and autolysosomes are significantly increased while lysosomal numbers are normal in Purkinje cell bodies

• at 20 months of age, brains show accumulation of autophagic deposits that are positive for both Lamp1 (a lysosomal membrane protein) and the autophagic cargo receptor p62

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hereditary spastic paraplegia 48		DOID:0110800	OMIM:613647	J:283611