Body composition in Spinocerebellar ataxia type 3 and 10 patients: Comparative study with control group

Leite, Christiane; Schieferdecker, Maria Eliana Madalozzo; Frehner, Caroline; Munhoz, Renato P.; Ashizawa, Tetsuo; Teive, Hélio Afonso Ghizoni

doi:10.1080/1028415x.2018.1469282

Cited by 6 publications

(1 citation statement)

References 35 publications

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“…1). Decreased body weight observed in Ki91 animals is one of the hallmarks of SCA3 phenotype in patients [17–20]. Based on preliminary pilot proteomic experiments in old Ki91 mice, we have selected 16 most promising dysregulated protein hits ( Atp2b1 , Psat1 , Ppp2r1a , Idh1 , Akr1b1 , Srsf2 , Plp1 , Glul , Ca2 , Ndufa9 , Pea15a , Tuba1a , Psmd4 , Omg , Cox7a2 , and Qdpr ) to examine potential transcriptional events in old Ki91 animals at 10 and 14 months old.…”

Section: Resultsmentioning

confidence: 99%

Altered Levels of Proteins and Phosphoproteins, in the Absence of Early Causative Transcriptional Changes, Shape the Molecular Pathogenesis in the Brain of Young Presymptomatic Ki91 SCA3/MJD Mouse

et al. 2019

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Spinocerebellar ataxia type 3 (SCA3/MJD) is a polyQ neurodegenerative disease where the presymptomatic phase of pathogenesis is unknown. Therefore, we investigated the molecular network of transcriptomic and proteomic triggers in young presymptomatic SCA3/MJD brain from Ki91 knock-in mouse. We found that transcriptional dysregulations resulting from mutant ataxin-3 are not occurring in young Ki91 mice, while old Ki91 mice and also postmitotic patient SCA3 neurons demonstrate the late transcriptomic changes. Unlike the lack of early mRNA changes, we have identified numerous early changes of total proteins and phosphoproteins in 2-month-old Ki91 mouse cortex and cerebellum. We discovered the network of processes in presymptomatic SCA3 with three main groups of disturbed processes comprising altered proteins: (I) modulation of protein levels and DNA damage (Pabpc1, Ddb1, Nedd8), (II) formation of neuronal cellular structures (Tubb3, Nefh, p-Tau), and (III) neuronal function affected by processes following perturbed cytoskeletal formation (Mt-Co3, Stx1b, p-Syn1). Phosphoproteins downregulate in the young Ki91 mouse brain and their phosphosites are associated with kinases that interact with ATXN3 such as casein kinase, Camk2, and kinases controlled by another Atxn3 interactor p21 such as Gsk3, Pka, and Cdk kinases. We conclude that the onset of SCA3 pathology occurs without altered transcript level and is characterized by changed levels of proteins responsible for termination of translation, DNA damage, spliceosome, and protein phosphorylation. This disturbs global cellular processes such as cytoskeleton and transport of vesicles and mitochondria along axons causing energy deficit and neurodegeneration also manifesting in an altered level of transcripts at later ages.Electronic supplementary materialThe online version of this article (10.1007/s12035-019-01643-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%