Stawikowska, A. | Search bioRxiv

bioRxiv2024

Terminal nucleotidyltransferase Tent2 microRNA tailing regulates excitatory/inhibitory balance in the hippocampus

One of the post-transcriptional mechanisms regulating the stability of RNA molecules involves the addition of non-templated nucleotides to their 3 ends, a process known as RNA tailing. To systematically investigate the physiological consequences of terminal nucleotidyltransferase TENT2 absence on RNA 3 end modifications in the mouse hippocampus we developed a new Tent2 knockout mouse. Electrophysiological measurements revealed increased excitability in Tent2 KO hippocampal neurons, and behavioral analyses showed decreased anxiety and improved fear extinction in these mice. At the molecular level, we observed a significant contribution of TENT2 to the monoadenylation of various classes of miRNAs, but found no effect of the enzymes loss on the total poly(A) tail length of mRNAs, as measured by Direct Nanopore RNA sequencing. Alterations in monoadenylation of a large population of microRNAs affected the overall mRNA abundance, particularly transcripts related synaptic transmission, which were downregulated in the hippocampus of Tent2 knockout mice. These changes explain the observed behavioral and electrophysiological alterations. Our data thus establish a link between TENT2-dependent microRNA tailing and the balance of inhibitory and excitatory neurotransmission.

neuroscience↗

bioRxiv2023

Mutation in mitochondrial chaperone TRAP1 results in male-specific autism

There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities exclusively in males. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, number of presynaptic mitochondria, and metabolic substrate consumption. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis. One-Sentence SummaryPatient mutation in TRAP1 causes autism in male mice.

neuroscience↗