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

  1. Terri M Driessen
  2. Paul J Lee
  3. Janghoo Lim  Is a corresponding author
  1. Yale School of Medicine, United States

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.

Data availability

RNA sequencing data have been deposited in GEO under accession (number: 122099).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Terri M Driessen

    Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Paul J Lee

    Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Janghoo Lim

    Department of Genetics, Yale School of Medicine, New Haven, United States
    For correspondence
    janghoo.lim@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5331-210X

Funding

National Institute of Neurological Disorders and Stroke (NS083706)

  • Janghoo Lim

National Institute of Neurological Disorders and Stroke (NS088321)

  • Janghoo Lim

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2016-11342) of the Yale University. The Yale University Institutional Animal Care and Use Committee approved all research and animal care procedures. We made every effort to minimize animal suffering.

Reviewing Editor

  1. J Paul Taylor, St Jude Children's Research Hospital, United States

Publication history

  1. Received: July 11, 2018
  2. Accepted: December 2, 2018
  3. Accepted Manuscript published: December 3, 2018 (version 1)
  4. Version of Record published: December 13, 2018 (version 2)

Copyright

© 2018, Driessen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,880
    Page views
  • 297
    Downloads
  • 10
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Terri M Driessen
  2. Paul J Lee
  3. Janghoo Lim
(2018)
Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1
eLife 7:e39981.
https://doi.org/10.7554/eLife.39981

Further reading

    1. Neuroscience
    Arefeh Sherafati et al.
    Research Article Updated

    Cochlear implants are neuroprosthetic devices that can restore hearing in people with severe to profound hearing loss by electrically stimulating the auditory nerve. Because of physical limitations on the precision of this stimulation, the acoustic information delivered by a cochlear implant does not convey the same level of acoustic detail as that conveyed by normal hearing. As a result, speech understanding in listeners with cochlear implants is typically poorer and more effortful than in listeners with normal hearing. The brain networks supporting speech understanding in listeners with cochlear implants are not well understood, partly due to difficulties obtaining functional neuroimaging data in this population. In the current study, we assessed the brain regions supporting spoken word understanding in adult listeners with right unilateral cochlear implants (n=20) and matched controls (n=18) using high-density diffuse optical tomography (HD-DOT), a quiet and non-invasive imaging modality with spatial resolution comparable to that of functional MRI. We found that while listening to spoken words in quiet, listeners with cochlear implants showed greater activity in the left prefrontal cortex than listeners with normal hearing, specifically in a region engaged in a separate spatial working memory task. These results suggest that listeners with cochlear implants require greater cognitive processing during speech understanding than listeners with normal hearing, supported by compensatory recruitment of the left prefrontal cortex.

    1. Neuroscience
    Mohammad Ali Salehinejad et al.
    Research Article Updated

    Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta oscillations due to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data indicate that upscaled brain excitability and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance. Besides showing how brain physiology and cognition undergo changes (from neurophysiology to higher-order cognition) under sleep pressure, the findings have implications for variability and optimal application of noninvasive brain stimulation.