Loss of intracerebellar heterogeneity and selective vulnerability in Spinocerebellar ataxia type 1 neurodegeneration

Abstract

Spinocerebellar Ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by abnormal expansion of the polyglutamine (polyQ) repeats in the ATAXIN1 (ATXN1) protein. Patients with SCA1 suffer from progressive motor and cognitive impairments, without any disease modifying treatments available. Although mutant ATXN1 is expressed throughout the brain, the cerebellum undergoes the most severe degeneration. It remains unclear why the cerebellum is particularly vulnerable in SCA1. A majority of previous studies using mouse models of SCA1 have investigated pathological changes in the cerebellar cortex by examining a singular region in the cerebellar cortex, the vermal primary fissure (lobules V and VI). Gene expression changes have mostly been examined using the bulk cerebellum. However, recent studies in patients indicate that SCA1 pathogenesis is not uniform across cerebellum, and in fact demonstrate that the posterior vermis and hemispheres exhibit worse pathology. Pathological and molecular alterations in the posterior cerebellum and hemispheres remain mostly unknown in mouse models of SCA1. This study addresses these questions using Atxn1154Q/2Q line, a knock-in SCA1 mouse model in which mutant ATXN1 is widely expressed. We found more pronounced pathology of Purkinje cells and reactive gliosis in the posterior vermis of Atxn1154Q/2Q mice at mid -disease stages, similar to what has been described in SCA1 patients. Comparison of the gene expression changes demonstrates that several cerebellar cell types, including Purkinje cells, and Bergmann glia, are more affected in the posterior vermis, and hemispheres. Pathway analysis identified discrete, region specific SCA1 pathogenesis pathways as well as commonly enriched biological pathways.

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

“…For instance, Hamel et al used ATXN1154Q/2Q SCA1 knock-in mice that express the mutant protein under the endogenous promoter, allowing for physiological levels and spatial distribution of mutant ATXN1 expression. By employing this model, they investigated the intracerebellar regional differences in pathology and the underlying molecular factors contributing to the disease [ 317 ]. Their findings revealed increased dendritic atrophy and loss of synapses, along with elevated reactive gliosis (its presence is not specific for a particular pathologic entity) in these regions.…”

Cerebellar contribution to cognitive deficits and prefrontal cortex dysfunction in Spinocerebellar Ataxia Type 1 (SCA1)

“…IF was performed on a minimum of six different floating 40-μm-thick brain slices from each mouse (six technical replicates per mouse per region or antibody of interest). We used primary antibodies against c-Fos (rabbit, Abcam, ab190289), neuronal marker neuronal nuclei (NeuN) (rabbit, Abcam, Ab104225), PSD95 (rabbit, Thermo Fisher Scientific, 51-69000), vesicular glutamate transporter 2 (VGLUT2) (guinea pig, Millipore, AB2251-I), Gephyrin (rabbit, Thermo Fisher Scientific, PA5-29036), and VGAT (guinea pig, Synaptic Systems,131005) as previously described 29,30 .…”

Extracellular Matrix Regulation in Physiology and in Brain Disease

“…Given that in the developing lung, the ATXN1 family regulates ECM remodeling, it is possible that ATXN1 might have a similar function in ECM regulation in the cerebellum and that mutations in ATXN1 could result in dysregulation of ECM genes [ 56 ]. Indeed, RNAseq on cerebellar cortex tissue identified DEGs involved in ECM regulation [ 57 ]. These included genes encoding ECM components collagen ( Col4a5 , Col6a5, Col11a1, Col9a2 ), laminin ( Lamc3 ), integrins ( Itga3, Itgb3, 5 and 6 ), and ECM remodeling ( Adamts10, Adamts4, MMP16, MMP17 ).…”