Cross-disease analysis of depression, ataxia and dystonia highlights a role for synaptic plasticity and the cerebellum in the pathophysiology of these comorbid diseases

Miaozhen Huang; Tom J de Koning; Marina A J Tijssen; Dineke S Verbeek

doi:10.1016/j.bbadis.2020.165976

Cross-disease analysis of depression, ataxia and dystonia highlights a role for synaptic plasticity and the cerebellum in the pathophysiology of these comorbid diseases

Biochim Biophys Acta Mol Basis Dis. 2021 Jan 1;1867(1):165976. doi: 10.1016/j.bbadis.2020.165976. Epub 2020 Oct 2.

Authors

Miaozhen Huang¹, Tom J de Koning², Marina A J Tijssen³, Dineke S Verbeek⁴

Affiliations

¹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Pediatrics, Department of Clinical Sciences, Lund University, Sweden.
³ Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: d.s.verbeek@umcg.nl.

PMID: 33011198
DOI: 10.1016/j.bbadis.2020.165976

Abstract

Background: There is growing evidence that the neuropsychiatric and neurological disorders depression, ataxia and dystonia share common biological pathways. We therefore aimed to increase our understanding of their shared pathophysiology by investigating their shared biological pathways and molecular networks.

Methods: We constructed gene sets for depression, ataxia, and dystonia using the Human Phenotype Ontology database and genome-wide association studies, and identified shared genes between the three diseases. We then assessed shared genes in terms of functional enrichment, pathway analysis, molecular connectivity, expression profiles and brain-tissue-specific gene co-expression networks.

Results: The 33 genes shared by depression, ataxia and dystonia are enriched in shared biological pathways and connected through molecular complexes in protein-protein interaction networks. Biological processes common/shared to all three diseases were identified across different brain tissues, highlighting roles for synaptic transmission, synaptic plasticity and nervous system development. The average expression of shared genes was significantly higher in the cerebellum compared to other brain regions, suggesting these genes have distinct cerebellar functions. Several shared genes also showed high expression in the cerebellum during prenatal stages, pointing to a functional role during development.

Conclusions: The shared pathophysiology of depression, ataxia and dystonia seems to converge onto the cerebellum that maybe particularly vulnerable to changes in synaptic transmission, regulation of synaptic plasticity and nervous system development. Consequently, in addition to regulating motor coordination and motor function, the cerebellum may likely play a role in mood processing.

Keywords: Ataxia; Cerebellum comorbidity; Cross-disease analysis; Depression; Dystonia; Synaptic plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia* / genetics
Ataxia* / metabolism
Ataxia* / pathology
Brain* / metabolism
Brain* / pathology
Cerebellum* / metabolism
Cerebellum* / pathology
Depression* / genetics
Depression* / metabolism
Depression* / pathology
Dystonia* / genetics
Dystonia* / metabolism
Dystonia* / pathology
Genome-Wide Association Study
Humans
Neuronal Plasticity*
Protein Interaction Maps
Synaptic Transmission*