# Novel knock-in mouse models of spinocerebellar ataxia type 12

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $450,313

## Abstract

PROJECT SUMMARY
 Spinocerebellar ataxia type 12 (SCA12) is a rare neurodegenerative disease caused by a CAG/CTG
expansion in exon 7 of PPP2R2B, a gene encoding regulatory units of the protein phosphatase 2A. SCA12 is
characterized by tremor, gait abnormalities, and psychiatric syndromes. Neuropathologically, the single SCA12
brain that has become available revealed prominent atrophy of the cerebral cortex and cerebellum, with a noted
loss of Purkinje cells consistent with MRI findings in multiple pedigrees. PPP2R2B transcript is alternatively
spliced with at least eight variants, each with a different N-terminal region. The repeat in exon 7 is itself included
in at least three splice variants. In two variants, the repeat falls into ORFs predicted to encode the poly serine
(polySer) tracts, giving rise to short polySer tracts from the normal allele and long polySer tracts from the
expanded allele. Our preliminary data from cell systems suggests that even in the absence of AUG start codons,
long polySer may be produced by repeat associated non-AUG (RAN) translation, and that proteins with a long
polySer, but not a short polySer, have toxic properties.
 By CRISPR-assisted homologous recombination, we have successfully generated a humanized SCA12
knock-in (KI-10 or 80) mouse model, in which the mouse exon 2 was replaced by its human counterpart exon 7
with 10 or 80 CAG triplets. We hypothesize that the SCA12 KI-80 mouse model will recapitulate some features
of the human SCA12 disease; and that poly amino acid tracts, especially long polySer, may be expressed in
SCA12 KI-80, triggering toxicity hence SCA12 pathogenesis, and that the repeat expansion may alter PPP2R2B
splicing and expression. In Aim 1, we will perform behavioral testing, neuropathology studies and neuroimaging
to characterize the novel SCA12 KI-80 mouse model, along with its control SCA12 KI-10 model and WT. In Aim
2, we will determine the expression and potential toxicity of the predicted polySer containing proteins in SCA12
KI mice by correlating the polySer expression and aggregation with the progression of the mouse phenotype,
behavior abnormalities and brain atrophy. We will examine the splicing and expression of PPP2R2B by RT-PCR
and qPCR in KI-80, compared with KI-10 and WT. The proposed experiments provide some of the first steps in
determining potential therapeutic targets for SCA12, and the appropriate models for testing rational therapeutics.

## Key facts

- **NIH application ID:** 9975258
- **Project number:** 1R21NS112687-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Pan Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,313
- **Award type:** 1
- **Project period:** 2020-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975258

## Citation

> US National Institutes of Health, RePORTER application 9975258, Novel knock-in mouse models of spinocerebellar ataxia type 12 (1R21NS112687-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9975258. Licensed CC0.

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