Biology subjects

Massi, F.

Publications and source records attributed to Massi, F..

8 recordsLinked to original sources

bioRxiv2025

TDP-43 dysfunction leads to impaired proteostasis and predisposes mice to worse neurological outcomes after brain injury

BackgroundPathological TAR DNA-binding protein 43 (TDP-43) dysfunction is associated with multiple neurodegenerative disorders. However, the mechanistic link between TDP-43 dysfunction and neurodegeneration is poorly understood and likely involves a combination of genetic and environmental risk factors. A major risk factor for neurodegenerative disease is exposure to traumatic brain injury (TBI). Here, we investigated the synergistic interplay between TDP-43 dysfunction and TBI in a murine model of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). MethodsA model of TDP-43 dysfunction caused by a knock-in Q331K mutation in Tardbp was combined with a mild model of TBI. Control conditions included both WT mice and mice with sham surgery. Animals were evaluated for behavioral deficits at timepoints pre- and post-surgery. Additionally, post-mortem brain tissues were examined using RNA sequencing and mass spectrometry-based quantitative proteomics together with histological and biochemical analyses. ResultsExpression of dysfunctional TDP-43 in vivo caused deficits in multiple branches of the proteostasis network, including protein folding, protein synthesis, and protein turnover. Examples include mis-expression of chaperones and genes within the ubiquitin-proteosome pathway in mutant TDP-43 versus WT mice. Further, mutant TDP-43 expression correlated with reduced thermostability of proteins associated with the ribosome and the chaperonin containing TCP-1 complex. In response to TBI, mutant TDP-43 mice exhibited significantly worse neurological outcomes relative to WT animals. Heightened neurological deficits in mutant TDP-43 mice following TBI coincided with a robust upregulation of proteostasis- and stress-related genes at the transcript level. However, this upregulation was not detected at the protein level. ConclusionsOur data demonstrate that expression of dysfunctional TDP-43 leads to deficits within the proteostasis network in vivo at baseline. Despite an upregulation of proteostasis-related genes at the transcript level in mutant TDP-43 mice after TBI, mutant TDP-43 mice exhibit an impaired response to, and recovery from, brain trauma relative to their WT counterparts. Restoring proteostasis is expected to protect against the detrimental effects of TDP-43 dysfunction, especially under stress conditions that promote neurodegenerative disease.

neuroscience↗

bioRxiv2025

Movement sonification during haptic exploration shifts emotional outcome without altering texture perception

Adding movement sonification to haptic exploration can change the perceptual outcome of a textured surface through multisensory processing. We hypothesized that auditory-evoked emotions would influence the appraisal of textured surfaces, with corresponding changes reflected in cortical excitability. Participants actively rubbed two different textured surfaces (slippery and rough) either without movement sonification, or with pleasant or disagreeable movement sonification. We found that sounds, whether agreeable or disagreeable, did not change the texture appraisal. However, the less pleasant surface was associated with a stronger negative hedonic valence, particularly when paired with disagreeable movement sonification. Time frequency analyses of EEG activities revealed a significant reduction in beta-band power [15-25 Hz] within the source-estimated sensorimotor and superior posterior parietal cortices when contrasting both pleasant and unpleasant sound with the silent touch. This suggests that the primary somatosensory cortices together with the superior parietal regions participated in the audio-tactile binding, with both pleasant and unpleasant sounds. In addition, we observed a significant increase in beta-band power in medial visual areas, specifically when disagreeable movement sonification was paired with tactile exploration. This may reflect a disengagement of visual cortical processing, potentially amplifying auditory-driven emotional responses and intensifying the perceived unpleasantness of the explored surfaces.

neuroscience↗

bioRxiv2025

A conserved triple arginine motif in OMA-1 is required for RNA-binding activity and embryo viability

Sexually reproducing organisms make haploid gametes--oocytes and spermatocytes--that combine during fertilization to make an embryo. While both gametes contain similar DNA content, oocytes contain the bulk of the cytoplasm including maternally supplied mRNAs and proteins required prior to zygotic gene activation. RNA-binding proteins are key regulators of these maternal transcripts. In Caenorhabditis elegans, the tandem zinc finger proteins OMA-1 and OMA-2 are required for fertilization. Here, we show that OMA-1 RNA-binding activity requires a short basic region immediately up-stream from the canonical tandem zinc finger domain. Mutation of this region in animals produces a phenotype distinct from a genetic null. Oocytes can be fertilized, but fail to form an intact chitin egg-shell, frequently break in utero, and arrest prior to morphogenesis. Our results identify a critical region outside of the canonical RNA-binding domain required for both RNA-binding activity as well as revealing a new role for OMA-1 during the oocyte-to-embryo transition.

biochemistry↗

bioRxiv2024

Guided by touch: Tactile Cues in Hand Movement Control

Traditionally, touch is associated with exteroception and is rarely considered a relevant sensory cue for controlling movements in space, unlike vision. We developed a technique to isolate and evaluate tactile involvement in controlling sliding finger movements over a surface. Young adults traced a 2D shape with their index finger under direct or mirror-reversed visual feedback to create a conflict between visual and somatosensory inputs. In this context, increased reliance on somatosensory input compromises movement accuracy. Based on the hypothesis that tactile cues contribute to guiding hand movements, we predicted poorer performance when the participants traced with their bare finger compared to when their tactile sensation was dampened using a smooth finger splint. The results supported this prediction. EEG source analyses revealed smaller current in the presumed somatosensory cortex during sensory conflict, but only when the finger directly touched the surface. This finding suggests the gating of task-irrelevant somatosensory inputs. Together, our results emphasize touchs involvement in movement control, challenging the notion that vision predominantly governs goal-directed hand or finger movements.

neuroscience↗

bioRxiv2024

A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.

biochemistry↗

bioRxiv2023

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited lipid dysmetabolism and deficits in phagocytosis, a critical microglia function. Our cumulative data implicate an effect of ALS-linked PFN1 on the autophagy pathway, including enhanced binding of mutant PFN1 to the autophagy signaling molecule PI3P, as an underlying cause of defective phagocytosis in ALS-PFN1 iMGs. Indeed, phagocytic processing was restored in ALS-PFN1 iMGs with Rapamycin, an inducer of autophagic flux. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and highlight microglia vesicular degradation pathways as potential therapeutic targets for these disorders.

neuroscience↗

bioRxiv2022

A nematode model to evaluate microdeletion phenotype expression

Microdeletion syndromes are genetic diseases caused by chromosomal deletions too small to be detected by karyotyping. They are typified by complex pleiotropic developmental phenotypes that depend both on the extent of the deletion and variations in genetic background. Microdeletion alleles disrupt several genes simultaneously, often as the result of a single mutagenic event, causing a wide array of consequences across multiple systems involving multiple pathways. How simultaneous haploinsufficiency of numerous adjacent genes leads to complex and variable pleiotropic phenotypes is not well understood. CRISPR/Cas9 genome editing has been shown to induce microdeletion-like alleles at a meaningful rate. Here, we describe a microdeletion allele in Caenorhabditis elegans recovered during a CRISPR/Cas9 genome editing experiment. We mapped the allele to chromosome V, balanced it with a reciprocal translocation crossover suppressor, and precisely defined the breakpoint junction. The allele simultaneously removes 32 protein-coding genes, yet animals homozygous for this mutation are viable as adults. Homozygous animals display a complex phenotype including maternal effect lethality, producing polynucleated embryos that grow into uterine tumors, vulva morphogenesis defects, body wall distensions, uncoordinated movement, and a shortened life span typified by death by bursting. Our work provides an opportunity to explore the complexity and penetrance of microdeletion phenotypes in a simple genetic model system.

genetics↗

bioRxiv2022

When mechanical engineering inspired from physiology improves postural-related somatosensory processes

Being the first stimulated by the relative movement of foot skin and the underneath moving support surface, the plantar tactile receptors (i.e., mechanoreceptors) play an important role in the sensorimotor transformation giving rise to a postural reaction. In this light, a biomimetic surface, i.e., complying with the characteristics of the mechanoreceptors and the skin dermatoglyphs (i.e., pattern of the ridges) should facilitate the cortical processes in response to the somatosensory stimulation involved in the balance recovery motor control. Healthy young adults (n = 21) were standing still either on a biomimetic surface or on two control surfaces (i.e., grooved or smooth), when a sudden but low acceleration of the supporting surface along the lateral direction was triggered. A shorter and more robust evoked somatosensory response (i.e., SEP) was observed when participants were standing on the biomimetic surface. As well, a lower oscillatory response in the theta (5-7 Hz) time-frequency domain in the left posterior parietal cortex (PPC) was observed with the biomimetic surface. The greater shear forces induced by the interaction between the feet and the biomimetic surface during the platform motion was likely at the origin of the increased SEP. Besides, the decrease of theta power suggests that the balance task became less challenging. This interpretation was tested in a second experiment by adding a cognitive task, which should be less detrimental for the postural reaction when standing on a biomimetic surface. Consistent with this hypothesis, a more efficient postural reaction (i.e., shorter latency and greater amplitude) was observed when the cognitive task was performed while standing on the biomimetic surface.

neuroscience↗