MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration.

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson's disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces-whereas silencing MAPT-AS1 expression increases-neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.

Auditory tracts identified with combined fMRI and diffusion tractography.

The auditory tracts in the human brain connect the inferior colliculus (IC) and medial geniculate body (MGB) to various components of the auditory cortex (AC). While in non-human primates and in humans, the auditory system is differentiated in core, belt and parabelt areas, the correspondence between these areas and anatomical landmarks on the human superior temporal gyri is not straightforward, and at present not completely understood. However it is not controversial that there is a hierarchical organization of auditory stimuli processing in the auditory system. The aims of this study were to demonstrate that it is possible to non-invasively and robustly identify auditory projections between the auditory thalamus/brainstem and different functional levels of auditory analysis in the cortex of human subjects in vivo combining functional magnetic resonance imaging (fMRI) with diffusion MRI, and to investigate the possibility of differentiating between different components of the auditory pathways (e.g. projections to areas responsible for sound, pitch and melody processing). We hypothesized that the major limitation in the identification of the auditory pathways is the known problem of crossing fibres and addressed this issue acquiring DTI with b-values higher than commonly used and adopting a multi-fibre ball-and-stick analysis model combined with probabilistic tractography. Fourteen healthy subjects were studied. Auditory areas were localized functionally using an established hierarchical pitch processing fMRI paradigm. Together fMRI and diffusion MRI allowed the successful identification of tracts connecting IC with AC in 64 to 86% of hemispheres and left sound areas with homologous areas in the right hemisphere in 86% of hemispheres. The identified tracts corresponded closely with a three-dimensional stereotaxic atlas based on postmortem data. The findings have both neuroscientific and clinical implications for delineation of the human auditory system in vivo.