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Sonobe, Y.

Publications and source records attributed to Sonobe, Y..

5 recordsLinked to original sources

Supramodal representation of the sense of body ownership in the human parieto-premotor and extrastriate cortices

The sense of body ownership, defined as the sensation that ones body belongs to oneself, is a fundamental component of bodily self-consciousness. Several studies have shown the importance of multisensory integration for the emergence of the sense of body ownership, together with the involvement of the parieto-premotor and extrastriate cortices in bodily awareness. However, whether the sense of body ownership elicited by different sources of signal, especially visuotactile and visuomotor inputs, is represented by common neural patterns remains to be elucidated. We used functional magnetic resonance imaging (fMRI) to investigate the existence of neural correlates of the sense of body ownership independent of the sensory modalities. Participants received tactile stimulation or executed finger movements while given synchronous and asynchronous visual feedback of their hand. We used multi-voxel patterns analysis (MVPA) to decode the synchronous and asynchronous conditions with cross-classification between two modalities: the classifier was first trained in the visuotactile sessions and then tested in the visuomotor sessions and vice versa. Regions of interest-based and searchlight analyses revealed significant above-chance cross-classification accuracies in the bilateral intraparietal sulcus (IPS), the bilateral ventral premotor cortex (PMv), and the left extrastriate body area (EBA). Moreover, we observed a significant positive correlation between the cross-classification accuracy in the left PMv and the difference in subjective ratings of the sense of body ownership between the synchronous and asynchronous conditions. Our findings revealed the neural representations of the sense of body ownership in the IPS, PMv, and EBA that is invariant to the sensory modalities. Significance StatementPrevious studies have shown neural correlates of the sense of body ownership in parieto-premotor and extrastriate cortices. However, whether the sense of body ownership induced by different sensory inputs is represented in common neural patterns remains unelucidated. Using functional magnetic resonance imaging (fMRI) with multi-voxel pattern analysis (MVPA), we investigated neural representations of the sense of body ownership invariant to modalities. Decoding neural patterns for visuotactile and visuomotor modalities revealed successful cross-classification accuracies in intraparietal sulcus (IPS), ventral premotor cortex (PMv), and extrastriate body area (EBA). Furthermore, cross-classification accuracy in PMv was positively correlated with subjective ratings of the sense of body ownership. These findings demonstrate that supramodal representations in parieto-premotor and extrastriate cortices underlie the sense of body ownership.

neuroscience↗

Translation of dipeptide repeat proteins in C9ORF72-ALS/FTD through unique and redundant AUG initiation codons

A hexanucleotide repeat expansion in the first intron of C9ORF72 is the most common monogenic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Although initiation codons and regulatory factors have been identified for sense DPR translation, they remain mostly unknown for antisense DPRs. Here, we show that an AUG initiation codon is necessary for poly-PR synthesis, suggesting canonical AUG dependent translation. Remarkably, although an AUG located 194 base pairs (bp) upstream of the repeat is the main start codon for poly-PG synthesis, two other AUG codons (-212 bp, -113 bp) can also initiate translation, demonstrating a striking redundancy in start codon usage. eIF2D is required for CUG start codon-dependent poly-GA translation from the sense transcript in human motor neurons derived from induced pluripotent stem cells of C9ORF72 ALS/FTD patients, but AUG-dependent poly-PG or poly-PR synthesis does not require eIF2D, indicating that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings provide key molecular insights into DPR synthesis from the C9ORF72 locus, which may be broadly applicable to many other nucleotide-repeat expansion disorders.

molecular biology↗

Machine learning predicts translation initiation sites in neurologic diseases with expanded repeats

A number of neurologic diseases, including a form of amyotrophic lateral sclerosis and others associated with expanded nucleotide repeats have an unconventional form of translation called repeat-associated non-AUG (RAN) translation. Repeat protein products accumulate and are hypothesized to contribute to disease pathogenesis. It has been speculated that the repeat regions in the RNA fold into secondary structures in a length-dependent manner, promoting RAN translation. Additionally, nucleotides that flank the repeat region, especially ones closest to the initiation site, are believed to enhance translation initiation. Recently, a machine learning model based on a large number of flanking nucleotides has been proposed for identifying translation initiation sites. However, most likely due to its extensive feature selection and limited training data, the model has diminished predictive power. Here, we overcome this limitation and increase prediction accuracy by a) capturing the effect of nucleotides most critical for translation initiation via feature reduction, b) implementing an alternative machine learning algorithm better suited for limited data, c) building comprehensive and balanced training data (via sampling without replacement) that includes previously unavailable sequences, and, d) splitting ATG and near-cognate translation initiation codon data to train two separate models. We also design a supplementary scoring system to provide an additional prognostic assessment of model predictions. The resultant models have high performance, with 85.00-87.79% accuracy exceeding that of the previously published model by >18%. The models presented here are then used to identify translation initiation sites in genes associated with a number of neurologic repeat expansion disorders. The results confirm a number of experimentally discovered sites of translation initiation upstream of the expanded repeats and predict many sites that are not yet established.

bioinformatics↗

A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation

A hexanucleotide repeat expansion GGGGCC in the noncoding region of C9orf72 is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Potentially toxic dipeptide repeats (DPRs) are synthesized from the GGGGCC sequence via repeat associated non-AUG (RAN) translation. We developed C. elegans models that express, either ubiquitously or exclusively in neurons, a transgene with 75 GGGGCC repeats flanked by intronic C9orf72 sequence. The worms generate DPRs (poly-glycine-alanine [poly-GA], poly-glycine-proline [poly-GP]) and display neurodegeneration, locomotor and lifespan defects. Mutation of a non-canonical translation-initiating codon (CUG) upstream of the repeats blocked poly-GA production and ameliorated disease, suggesting poly-GA is pathogenic. Importantly, eukaryotic translation initiation factor 2D (eif-2D/eIF2D) was necessary for RAN translation. Genetic removal of eif-2D increased lifespan in both C. elegans models. In vitro findings in human cells demonstrated a conserved role for eif-2D/eIF2D in RAN translation that could be exploited for ALS and FTD therapy.

neuroscience↗

RNA-binding protein altered expression and mislocalization in multiple sclerosis

ObjectiveNuclear depletion and mislocalization of RNA-binding proteins (RBPs) trans-activation response DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are thought to contribute to the pathogenesis of a number of disorders, including amyotrophic lateral sclerosis (ALS). We recently found that TDP-43 as well as polypyrimidine tract binding protein (PTB) have decreased expression and mislocalization in oligodendrocytes in demyelinated lesions in an experimental mouse model of multiple sclerosis (MS) caused by Theilers murine encephalomyelitis virus infection.\n\nMethodsThe latter finding prompted us to investigate TDP-43, FUS, and PTB in the demyelinated lesions of MS and in in vitro cultured human brain-derived oligodendrocytes.\n\nResultsWe found: i) mislocalized TDP-43 in oligodendrocytes in active lesions in some MS patients; ii) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; iii) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; iv) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared to optimal culture conditions.\n\nConclusionTDP-43 has been found to have a key role in oligodendrocyte function and viability, while PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration. Our findings also identify nucleocytoplasmic transport as a target for treatment.

neuroscience↗