Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Lodewijk J A Toonen,Peter A C ‘T Hoen,Jelle J Goeman,Leticia G Leon,Willeke M C Van Roon-Mom,Marion Poirel,Sander A J Van Der Zeeuw,Olafur Th Magnusson,Melvin M Evers,Kristina M Hettne,Szymon M Kielbasa,Maurice Overzier,Alexandre Seyer,Hailiang Mei

doi:10.1186/s13024-018-0261-9

Abstract

BackgroundSpinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein. Expression of mutant ataxin-3 is known to result in transcriptional dysregulation, which can contribute to the cellular toxicity and neurodegeneration. Since the exact causative mechanisms underlying this process have not been fully elucidated, gene expression analyses in brains of transgenic SCA3 mouse models may provide useful insights.MethodsHere we characterised the MJD84.2 SCA3 mouse model expressing the mutant human ataxin-3 gene using a multi-omics approach on brain and blood. Gene expression changes in brainstem, cerebellum, striatum and cortex were used to study pathological changes in brain, while blood gene expression and metabolites/lipids levels were examined as potential biomarkers for disease.ResultsDespite normal motor performance at 17.5 months of age, transcriptional changes in brain tissue of the SCA3 mice were observed. Most transcriptional changes occurred in brainstem and striatum, whilst cerebellum and cortex were only modestly affected. The most significantly altered genes in SCA3 mouse brain were Tmc3, Zfp488, Car2, and Chdh. Based on the transcriptional changes, α-adrenergic and CREB pathways were most consistently altered for combined analysis of the four brain regions. When examining individual brain regions, axon guidance and synaptic transmission pathways were most strongly altered in striatum, whilst brainstem presented with strongest alterations in the pi-3 k cascade and cholesterol biosynthesis pathways. Similar to other neurodegenerative diseases, reduced levels of tryptophan and increased levels of ceramides, di- and triglycerides were observed in SCA3 mouse blood.ConclusionsThe observed transcriptional changes in SCA3 mouse brain reveal parallels with previous reported neuropathology in patients, but also shows brain region specific effects as well as involvement of adrenergic signalling and CREB pathway changes in SCA3. Importantly, the transcriptional changes occur prior to onset of motor- and coordination deficits.

Highlights

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein
SCA3 mice do not present with overt motor symptoms at 17 months of age The MJD84.2 mouse model ubiquitously expresses full-length mutant human ataxin-3 with 76–77 glutamines, under control of the human ataxin-3 promoter
Individual brain regions are differently affected by mutant ataxin-3 To establish differential gene expression changes between wild-type and SCA3 mice, RNA sequencing of brain and blood tissue was performed (Table 1)

Summary

Introduction

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein. The CAG repeat is translated into a polyglutamine (polyQ) stretch in the ataxin-3 protein, which upon mutational expansion to 56–84 glutamines results in a gain of toxic protein function [2] This protein toxicity mostly shows its effects in the brain, and neuronal loss in SCA3 has been reported predominantly in the brainstem, cerebellum (spinocerebellar pathways and dentate nucleus), striatum, thalamus, substantia nigra and pontine nuclei [3]. Previous gene expression studies have identified altered inflammatory processes, cell signalling and cell surface associated genes in cell and conditional animal models of SCA3 [8, 11, 12] Despite these recent advances in SCA3 pathogenicity, it is currently still not fully elucidated which molecular mechanisms are altered in response to mutant ataxin-3. It is useful to examine genetic mouse models of SCA3 for transcriptional changes that occur in different regions of the brain to infer causative disease mechanisms [13]

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