Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1.

Terri M Driessen,Paul J Lee,Janghoo Lim

doi:10.7554/elife.39981

Abstract

The neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) affects the cerebellum and inferior olive, though previous research has focused primarily on the cerebellum. As a result, it is unknown what molecular alterations are present in the inferior olive, and whether these changes are found in other affected tissues. This study addresses these questions for the first time using two different SCA1 mouse models. We found that differentially regulated genes in the inferior olive segregated into several biological pathways. Comparison of the inferior olive and cerebellum demonstrates that vulnerable tissues in SCA1 are not uniform in their gene expression changes, and express largely discrete but some commonly enriched biological pathways. Importantly, we also found that brain-region-specific differences occur early in disease initiation and progression, and they are shared across the two mouse models of SCA1. This suggests different mechanisms of degeneration at work in the inferior olive and cerebellum.

Highlights

A hallmark of neurodegenerative diseases is brain-region-specific cell death and dysfunction
A large RNA-sequencing (RNA-seq) study conducted across brain regions and peripheral tissues in Huntington’s disease (HD) mouse models identified gene clusters related to transcription, chromatin factors, and mitochondria that appear to be specific to the striatum (Langfelder et al, 2016)
This led us to conduct a thorough comparison of transcriptional changes in the inferior olive and cerebellum using two different spinocerebellar ataxia type 1 (SCA1) mouse models, knockin (KI) and transgenic (Tg) (Figure 1)

Summary

Introduction

A hallmark of neurodegenerative diseases is brain-region-specific cell death and dysfunction. A recent study in spinocerebellar ataxia type 3 (SCA3) identified brain region-dependent variability in gene expression changes prior to the onset of motor phenotypes despite modest transcriptional alterations in brain regions that remain largely unscathed (Toonen et al, 2018). This suggests that a subset of gene clusters spans affected tissues regardless of the degree of tissue vulnerability, while other genes may be enriched in discrete affected tissues. Disease progression may play a role in dictating the degree of overlap between two affected tissues, with a higher degree of variability between tissues early on in disease

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