Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized as an expanded CAG trinucleotide repeats in SCA2 gene resulting in abnormal polyglutamine sequence. We used positron emission tomography (PET) and magnetic resonance imaging (MRI) to clarify metabolic and atrophic changes of the brain in two symptomatic and three asymptomatic individuals who were genetically confirmed for SCA2. PET revealed decreased glucose metabolism in both patients and two of the three asymptomatic carriers in the cerebellum, pons, or both. No PET abnormality was found in the remaining one carrier who had only a very mildly expanded CAG repeat. MRI showed cerebellar and/or pontine atrophic changes in both patients and one of three carriers. The present study suggest that hypometabolism and atrophy of the cerebellum and pons may occur years before the clinical onset of SCA2. PET and MRI may be useful in the early detection of subclinical brain changes associated with SCA2.

The RNA-binding protein Ataxin-2 binds to and stabilizes a number of mRNA sequences, including that of the transactive response DNA binding protein 43 kDa (TDP-43). Ataxin-2 is additionally involved in several processes requiring translation such as germline formation, long term habituation and circadian rhythm formation. However, it has yet to be unambiguously demonstrated that Ataxin-2 is actually involved in activating the translation of its target mRNAs. Here we provide direct evidence from a polysome profile analysis showing that Ataxin-2 enhances translation of target mRNAs. Our recently established method for transcriptional pulse-chase analysis under conditions of suppressing deadenylation revealed that Ataxin-2 promotes post-transcriptional polyadenylation of the target mRNAs. Furthermore, Ataxin-2 binds to a poly(A) binding protein PABPC1 and a noncanonical poly(A) polymerase PAPD4 via its intrinsically disordered region (906–1095 aa) to recruit PAPD4 to the targets. Posttranscriptional polyadenylation by Ataxin-2 explains not only how it activates translation but also stabilizes target mRNAs, including TDP-43 mRNA. Ataxin-2 is known to be a potent modifier of TDP-43 proteinopathies and to play a causative role in the neurodegenerative disease Spinocerebellar ataxia type 2, so these findings suggest that Ataxin-2-induced cytoplasmic polyadenylation and activation of translation might impact neurodegeneration (i.e., TDP-43 proteinopathies) and this process could be a therapeutic target for Ataxin-2-related neurodegenerative disorders.

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Edited by Noboru Mizushima Keywords:Translation termination Inhibitor of apoptosis protein eRF3 Calpain Apoptosis a b s t r a c tThe involvement of polypeptide chain-releasing factor eRF3 in translation termination and mRNA decay is well established. Moreover, the finding that the proteolytically processed isoform of eRF3 (p-eRF3) interacts with inhibitors of apoptosis proteins (IAPs) to activate caspase, implies that eRF3 is a cell death regulator. However, the protease(s) responsible for p-eRF3 production and how p-eRF3 regulates apoptosis remain unknown. Here, we show that calpain mediates p-eRF3 production in vitro and in living cells. p-eRF3 is produced in cells treated with ER stressors in a calpain-dependent manner. These findings suggest that p-eRF3 is a novel regulator of calpain-dependent cell death.

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