Transcriptomic analyses reveal neuronal specificity of Leigh syndrome associated genes

Leigh syndrome (subacute necrotising encephalomyelopathy) is a rare inherited, complex, and typically early onset mitochondrial disorder with clinical and genetic heterogeneity. It owes its heterogeneous nature to the complex nature of mitochondrial genetics and the significant interactions that occur between the mitochondrial and nuclear genomes. Stepwise developmental regression is a classical feature of patients with Leigh syndrome, but other neurological features include ataxia, tremor, seizures, and occasionally psychiatric manifestations. To date the involvement of more than 100 genes has been identified in patients with Leigh syndrome. Despite this, the pathophysiology of Leigh syndrome remains unknown, although it is thought to be due to primary mitochondrial dysfunction.Here, we sought to determine the cellular specificity of all Leigh syndrome associated genes within the brain and investigate a potential common genetic mechanism between Leigh syndrome and other disorders with overlapping clinical features. We utilized co-expression network analyses constructed using existing UK Brain Expression Consortium (UKBEC) data from 10 brain regions to identify regions of the brain where our genes of interest were enriched. Next, expression weighted cell type enrichment (EWCE) was employed to determine the cellular specificity of Leigh syndrome associated genes. Association with pre-or post-synaptic structures was identified using synaptic gene ontology (SynGO) analysis. Finally, heritability analysis was performed on the co-expression network modules demonstrating enrichment of Leigh syndrome associated genes to investigate potential genetic relationships with Parkinson disease, epilepsy, and schizophrenia.Co-expression network analyses reveal that genes encoding oxidative phosphorylation subunits and assembly factors exhibit the highest levels of expression in brain regions most affected on MRI and neuropathology in Leigh syndrome. Further, over two thirds of the genes were found to be enriched within the substantia nigra and 19 genes appeared to cluster, with selective enrichment in the putamen, substantia nigra, medulla and thalamus. EWCE analyses of single cell RNA-Seq data from mouse brain revealed significant enrichment of Leigh syndrome associated genes in hippocampal and somatosensory pyramidal neurones and interneurons of the brain. SynGO analysis demonstrated that expression of these genes is preferentially associated with pre-synaptic structures. Heritability studies suggested that some modules in which Leigh syndrome associated genes were enriched were also enriched for Parkinson disease and epilepsy.In conclusion, our findings suggest a primary mitochondrial dysfunction as the underlying basis of Leigh syndrome with causative genes primarily expressed in neuronal cells, explaining the relative sparing of glial cells observed in neuropathological studies.