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

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.