While the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment... Show moreWhile the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood representing signatures in human brain, showing biomarker potential. Since drug candidates are generally first screened in rodent models, we aimed to identify HD signatures in blood and brain of YAC128 HD mice and compare these with previously identified human signatures. RNA sequencing was performed on blood withdrawn at two time points and four brain regions from YAC128 and control mice. Weighted gene co-expression network analysis was used to identify clusters of co-expressed genes (modules) associated with the HD genotype. These HD-associated modules were annotated via text-mining to determine the biological processes they represented. Subsequently, the processes from mouse blood were compared with mouse brain, showing substantial overlap, including protein modification, cell cycle, RNA splicing, nuclear transport, and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition, we identified HD blood-specific pathology, confirming previous findings for peripheral pathology in blood. Finally, we identified hub genes for HD-associated blood modules and proposed a strategy for gene selection for development of a disease progression monitoring panel. Show less
Buijsen, R.A.M.; Toonen, L.J.A.; Gardiner, S.L.; Roon-Mom, W.M.C. van 2019
Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as... Show moreAutosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias. Show less
Toonen, L.J.A.; Overzier, M.; Evers, M.M.; Leon, L.G.; Zeeuw, S.A.J. van der; Mei, H.L.; ... ; Roon-Mom, W.M.C. van 2018
Background: Spinocerebellar 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... Show moreBackground: Spinocerebellar 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.Methods: Here 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.Results: Despite 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, Cart, and Chdh. Based on the transcriptional changes, a-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.Conclusions: The 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. Show less
Toonen, L.J.A.; Overzier, M.; Evers, M.M.; Leon, L.G.; Zeeuw, S.A.J. van der; Mei, H.L.; ... ; Roon-Mom, W.M.C. van 2018
Spinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder caused by a CAG triplet repeat expansion in the ATXN3 gene. This expanded CAG repeat is translated into a toxic... Show moreSpinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder caused by a CAG triplet repeat expansion in the ATXN3 gene. This expanded CAG repeat is translated into a toxic polyglutamine repeat in the ataxin-3 protein. Over time, expression of the expanded ataxin-3 protein leads to neurodegeneration of particularly the cerebellum and brainstem in SCA3 patients. Currently, there is no treatment available for SCA3. In light of its monogenetic nature, SCA3 is a good candidate for genetic therapies. In the research described in this thesis, antisense oligonucleotides were tested as a potential therapy for SCA3. The antisense oligonucleotides were used to induce exon skipping at RNA level in order to remove toxic protein regions (proteolytic cleavage sites or the polyglutamine repeat) from the ataxin-3 protein. In addition to the therapeutic research, transcriptomic analysis of brain material from transgenic SCA3 mice was performed to further elucidate potential disease mechanisms underlying SCA3. Show less
Toonen, L.J.A.; Casaca-Carreira, J.; Pellise-Tintore, M.; Mei, H.L.; Temel, Y.; Jahanshahi, A.; Roon-Mom, W.M.C. van 2018
