A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1

Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded ATAXIN-1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1154Q/+ mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.

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Brainstem and striatal volume changes are detectable in under 1 year and predict motor decline in spinocerebellar ataxia type 1

Brain Communications ◽

10.1093/braincomms/fcaa184 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Timothy R Koscik ◽

Lauren Sloat ◽

Ellen van der Plas ◽

James M Joers ◽

Dinesh K Deelchand ◽

...

Keyword(s):

Magnetic Resonance ◽

Disease Progression ◽

Spinocerebellar Ataxia ◽

Mixed Effects ◽

Spinocerebellar Ataxia Type ◽

Resonance Spectroscopy ◽

Intracranial Volume ◽

Spinocerebellar Ataxia Type 1 ◽

Linear Mixed Effects

Abstract Spinocerebellar ataxia type 1 is a progressive neurodegenerative, movement disorder. With potential therapies on the horizon, it is critical to identify biomarkers that (i) differentiate between unaffected and spinocerebellar ataxia Type 1-affected individuals; (ii) track disease progression; and (iii) are directly related to clinical changes of the patient. Magnetic resonance imaging of volumetric changes in the brain may be a suitable source of biomarkers for spinocerebellar ataxia Type 1. In a previous report on a longitudinal study of patients with spinocerebellar ataxia Type 1, we evaluated the volume and magnetic resonance spectroscopy measures of the cerebellum and pons, showing pontine volume and pontine N-acetylaspartate-to-myo-inositol ratio were sensitive to change over time. As a follow-up, the current study conducts a whole brain exploration of volumetric MRI measures with the aim to identify biomarkers for spinocerebellar ataxia Type 1 progression. We adapted a joint label fusion approach using multiple, automatically generated, morphologically matched atlases to label brain regions including cerebellar sub-regions. We adjusted regional volumes by total intracranial volume allowing for linear and power-law relationships. We then utilized Bonferroni corrected linear mixed effects models to (i) determine group differences in regional brain volume and (ii) identify change within affected patients only. We then evaluated the rate of change within each brain region to identify areas that changed most rapidly. Lastly, we used a penalized, linear mixed effects model to determine the strongest brain predictors of motor outcomes. Decrease in pontine volume and accelerating decrease in putamen volume: (i) reliably differentiated spinocerebellar ataxia Type 1-affected and -unaffected individuals; (ii) were observable in affected individuals without referencing an unaffected comparison group; (iii) were detectable within ∼6–9 months; and (iv) were associated with increased disease burden. In conclusion, volumetric change in the pons and putamen may provide powerful biomarkers to track disease progression in spinocerebellar ataxia Type 1. The methods employed here are readily translatable to current clinical settings, providing a framework for study and usage of volumetric neuroimaging biomarkers for clinical trials.

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Early stage of Spinocerebellar Ataxia Type 1 (SCA1) progression exhibits region- and cell-specific pathology and is partially ameliorated by Brain Derived Neurotrophic Factor (BDNF)

10.1101/2021.09.13.460129 ◽

2021 ◽

Author(s):

Juao-Guilherme Rosa ◽

Katherine Hamel ◽

Carrie Sheeler ◽

Ella Borgenheimer ◽

Stephen Gilliat ◽

...

Keyword(s):

Brain Stem ◽

Spinocerebellar Ataxia ◽

Neurotrophic Factor ◽

Early Stage ◽

Brain Regions ◽

Spinocerebellar Ataxia Type ◽

Wild Type ◽

Spinocerebellar Ataxia Type 1 ◽

The Brain

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1) and characterized by motor deficits, cognitive decline, changes in affect, and premature lethality. Due to the severe cerebellar degeneration in SCA1, the pathogenesis of Purkinje cells has been the main focus of previous studies. However, mutant ATXN1 is expressed throughout the brain, and pathology in brain regions beyond the cerebellar cortex likely contribute to the symptoms of SCA1. Here, we investigate early-stage SCA1 alterations in neurons, astrocytes, and microglia in clinically relevant brain regions including hippocampus and brain stem of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1 expressing mutant ATXN1 globally. Our results indicate shared and brain region specific astrocyte pathology early in SCA1 preceding neuronal loss. We found reduced expression of homeostatic astrocytic genes Kcnj10, Aqp4, Slc1a2 and Gja1, all of which are key for neuronal function in the hippocampus and brain stem. These gene expression changes did not correlate with classical astrogliosis. Neuronal and microglial numbers were largely unaltered at this early stage of SCA1 with the exception of cerebellar white matter, where we found significant reduction in microglial density, and the brain stem where we detected an increase in microglial cell counts. Brain-derived neurotrophic factor (BDNF) is a growth factor important for the survival and function of neurons with broad therapeutic potential for many brain diseases. We report here that BDNF expression is decreased in cerebellum and medulla of patients with SCA1. Moreover, we found that BDNF had dual effect on SCA1 and wild-type mice. Motor performance, strategy development, hippocampal neurogenesis, and expression of astrocyte homeostatic genes in the hippocampus were ameliorated in BDNF-treated SCA1 mice and further enhanced in BDNF-treated wild-type mice. On the other hand, BDNF had a negative effect on memory recall and expression of homeostatic genes in the brain stem astrocytes both in wild-type and in SCA1 mice.

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