Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12

Abstract

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.

Transcriptomic Dynamics of a non-coding trinucleotide repeat expansion disorder SCA12 in iPSC derived neuronal cells: signatures of interferon induced response

“…A similar scenario can be anticipated in SCA12 where the CAG repeat expansion in a non-coding (untranslated) region of PPP2R2B. In SCA12 it has been shown that the length of the CAG repeats alters the expression of the PPP2R2B (Lin et al, 2010;O'Hearn et al, 2015). Overexpression of CAG repeat containing isoform of a noncoding RNA in SCA12 is reminiscent of the expression pattern observed in FXTAS (Hagerman, 2013) and may exert cytotoxic effects through various mechanisms such as RAN translation, antisense and poly-serine mediated pathophysiology (Zu et al, 2011;Nalavade et al, 2013).…”

“…The generated neurons displayed characteristics of a pan-neuronal lineage. We did not expect morphological differences in these SCA12 neurons at early stages as like other neurodegenerative disease SCA12 produces a late onset phenotype and even neuropathological studies have not shown any morphological differences in the disease affected brain areas except for neuronal loss and gliotic changes (O'Hearn et al, 2015).…”

“…Radiologically and neuropathologically, SCA12 brain shows pattern of degeneration restricted to cerebral and cerebellar cortex (Holmes et al, 1999;O'Hearn et al, 2015;Srivastava et al, 2017). An iPSC-derived neuronal lineage might serve as an alternate surrogate experiment material to study the molecular events in SCA12.…”

“…Elongated CAG repeat motifs in their UTRs form secondary structures which can sequester different important proteins, leading to the formation of RNA foci and subsequently causing cell death. Ubiquitin positive inclusion bodies in the substantia nigra have also been observed in SCA12 (O'Hearn et al, 2015). Hence, there might exist overlaps in the disease mechanism between SCA12 and FXTAS.…”

Systematic screening identifies a 2‐gene signature as a high‐potential prognostic marker of undifferentiated pleomorphic sarcoma/myxofibrosarcoma

“…The two dominant transcripts (ENST00000394411.8 and ENST00000394409.7, Figure , red dotted frame) only contain 9 coding exons. PPP2R2B has well‐characterized expression in brain tissues . Therefore, we compared its expression profile in sarcoma with normal brain tissues.…”