Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.
OBJECTIVE
SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration.


METHODS
A fixed SCA12 brain was examined using gross, microscopic, and immunohistochemical methods. The effect of the repeat expansion on PPP2R2B Bβ1 expression was examined in multiple cell types by transient transfection of constructs containing the PPP2R2B Bβ1 promoter region attached to a luciferase reporter. The neurotoxic effect of PPP2R2B overexpression was examined in transfected rat primary neurons.


RESULTS
Neuropathological investigation revealed enlarged ventricles, marked cerebral cortical atrophy and Purkinje cell loss, less-prominent cerebellar and pontine atrophy, and neuronal intranuclear ubiquitin-positive inclusions, consistent with Marinesco bodies, which did not stain for long polyglutamine tracts, alpha-synuclein, tau, or transactive response DNA-binding protein 43. Reporter assays demonstrated that the region of PPP2R2B containing the repeat functions as a promoter, and that promoter activity increases with longer repeat length and is dependent on cell type, repeat sequence, and sequence flanking the repeat. Overexpression of PPP2R2B in primary cortical neurons disrupted normal morphology.


CONCLUSIONS
SCA12 involves extensive, but selective, neurodegeneration distinct from Alzheimer's disease, synucleinopathies, tauopathies, and glutamine expansion diseases. SCA12 neuropathology may arise from the neurotoxic effect of repeat-expansion-induced overexpression of PPP2R2B.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Elizabeth E
EE
O'Hearn
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hyon S
HS
Hwang
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Susan E
SE
Holmes
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Dobrila D
DD
Rudnicki
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Daniel W
DW
Chung
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Instituto de Biologia Molecular e Celular, Universidade do Porto, Oporto, Portugal.
Ana I
AI
Seixas
Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Rachael L
RL
Cohen
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Departments of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Christopher A
CA
Ross
Institute on Aging, Alzheimer's Disease Core Center, Udall Parkinson's Research Center, Center for Neurodegenerative Disease, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
John Q
JQ
Trojanowski
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Olga
O
Pletnikova
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Juan C
JC
Troncoso
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Laboratory of Genetic Neurobiology, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Russell L
RL
Margolis
D000818:Animals; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology*; D014162:Transfection; D018911:Trinucleotide Repeats / Q000235:genetics*
D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C000598624:TARDBP protein, human; C505936:PPP2R2B protein, human; D054648:Protein Phosphatase 2
Purkinje; ataxia; neurodegeneration; promoter; spinocerebellar