ABSTRACT
IMMP2L encodes the inner membrane peptidase subunit 2, a mitochondrial protease involved in cleaving the space-sorting signals of mitochondrial membrane proteins. IMMP2L has been implicated in Tourette syndrome, but how its dysfunction contributes to the neurodevelopmental phenotype remains unclear. Here we show that IMMP2L transcription requires Topoisomerase I in human primary astrocytes, and characterize the downstream effects of IMMP2L knockdown on gene expression. We demonstrate that IMMP2L knockdown leads to dysregulation of genes involved in central nervous system development. We also find that the transcriptional response to IMMP2L knockdown partially overlaps the one induced by mitochondrial complex III inhibition. Overall, these data bring further insight into the molecular consequences of IMMP2L dysfunction in the brain.
Subject(s)
Astrocytes/cytology , Brain/metabolism , Endopeptidases/genetics , Endopeptidases/metabolism , Antimycin A/chemistry , Astrocytes/metabolism , Cells, Cultured , Central Nervous System/metabolism , DNA Topoisomerases, Type I/metabolism , Electron Transport Complex III/metabolism , Gene Expression Profiling , Gene Knockdown Techniques , Humans , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Mutation , Oligonucleotide Array Sequence Analysis , RNA, Small Interfering/metabolism , Signal Transduction , Tourette Syndrome/geneticsABSTRACT
Autism spectrum disorder (ASD) is one of the most heritable neuropsychiatric conditions. The complex genetic landscape of the disorder includes both common and rare variants at hundreds of genetic loci. This marked heterogeneity has thus far hampered efforts to develop genetic diagnostic panels and targeted pharmacological therapies. Here, we give an overview of the current literature on the genetic basis of ASD, and review recent human brain transcriptome studies and their role in identifying convergent pathways downstream of the heterogeneous genetic variants. We also discuss emerging evidence on the involvement of non-coding genomic regions and non-coding RNAs in ASD.