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,Maurice Overzier,Melvin M. Evers,Leticia G. Leon,Sander A.J. van der Zeeuw,Hailiang Mei,Szymon M. Kielbasa,Jelle J. Goeman,Kristina Hettne,Olafur T. Magnusson,Marion Poirel,Alexandre Seyer,Peter A C 't Hoen,Peter A C 't Hoen,Willeke M. C. van Roon-Mom +14 more
TLDR
The observed transcriptional changes inSCA3 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.Abstract:
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. 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. 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, 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. 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.read more
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Journal ArticleDOI
Pathogenesis of SCA3 and implications for other polyglutamine diseases
TL;DR: Current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field is summarized and properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms are emphasized.
Journal ArticleDOI
Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3
Quan-Fu Li,Yi Dong,Lu Yang,Juan-Juan Xie,Yin Ma,Yi-Chu Du,Hao-Ling Cheng,Wang Ni,Zhi-Ying Wu +8 more
TL;DR: Levels of serum NfL were significantly elevated in SCA3 individuals and correlated with disease severity, and is a promising serum biomarker of disease onset and progression, and a potential candidate biomarkers of treatment response inSCA3.
Journal ArticleDOI
Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation.
Meihua Jin,Hiroki Shiwaku,Hikari Tanaka,Takayuki Obita,Sakurako Ohuchi,Yuki Yoshioka,Xiaocen Jin,Kanoh Kondo,Kyota Fujita,Hidenori Homma,Kazuyuki Nakajima,Mineyuki Mizuguchi,Hitoshi Okazawa +12 more
TL;DR: In this article, a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway was reported.
Journal ArticleDOI
Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia.
Clévio Nóbrega,Liliana Mendonça,Adriana Marcelo,Antonin Lamaziere,Sandra Tomé,Gaëtan Despres,Carlos A. Matos,Carlos A. Matos,Fatich Mechmet,Dominique Langui,Wilfred F. A. den Dunnen,Luís Pereira de Almeida,Nathalie Cartier,Nathalie Cartier,Sandro Alves +14 more
TL;DR: A pivotal role for CYP46A1 and brain cholesterol metabolism in neuronal function is confirmed, pointing to a key contribution of the neuronal cholesterol pathway in mechanisms mediating clearance of aggregate-prone proteins.
Journal ArticleDOI
From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation
TL;DR: The disruption of protein homeostasis is proposed as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated inSCA3 downstream consequences of the misfolding and aggregation of ATXN3.
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