TDP-43

…the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. By re-analyzing RNA-sequencing datasets from human FTD/ALS brains, we discovered dozens of novel cryptic splicing events in important neuronal genes. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wi

…of TAR DNA-binding protein 43 (TDP-43). Notably, unconventional metabolic conditions like type 2 diabetes mellitus and dyslipidemia paradoxically correlate with a better prognosis in ALS and FTLD, hinting at potential metabolic pathways in TDP-43-associated neurodegeneration. To better understand the interplay between TDP-43

…TDP-43 nuclear clearance and aggregates are identified as a major component of the ubiquitinated neuronal cytoplasmic inclusions deposited in spinal motor neurons both in familiar and sALS patients. Since TDP43 protein contains the HSC70 recognition motif, and, therefore, chaperon mediated autophagy (CMA) function may represent a cellular mechanism to regulate TDP43 cytoplasmic turnover in cells. We

ALS is a progressive neurodegenerative disease characterised by the loss of motoneurons (MNs). Some MNs present a lower vulnerability to the disease, including neurons of the oculomotor system (OCM), compared to other cranial MNs (facial or hypoglossal). Vascular endothelial growth factor (VEGF) has shown the ability to protect MNs from degeneration. Overexpression of VEGF is involved in neuroprotection and delayed neurodegeneration of MNs. We have previously described a higher amount of VEGF in the extraocular neurons in control adult rats. The objective of this study in the murine SOD1G93A A

…the aggregation of proteins like Aβ, TDP-43 and α-synuclein. For this, a complete physicochemical characterization of soy lecithin and other raw materials was carried

TDP-43 is an important DNA/RNA-binding protein that is mainly localized in the cell nucleus. In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), it is mislocalized and becomes a central component of cytoplasmic protein aggregates. Our aim was to investigate the interactome of wild-type TDP-43 and TDP-43 without nuclear localization signal (dNLS), which mimics a pathological condition in ALS. We generated inducible mammalian cell lines expressing TDP-43wt and TDP-TDP-43dNLS. Using the BioID method, we investigated the interactome of these

TDP-43 is the hallmark protein of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). This RNA-binding protein can form membrane-less condensates through liquid-liquid phase separation (LLPS). This biophysical process is considered to contribute to the regulation of TDP-43 functions but the precise mechanisms governing TDP-43 LLPS and its implications in homeostasis as well as pathology remain incompletely understood.In this study, we aimed to elucidate the influence of RNA-binding on TDP-43 dynamics and localization in vivo. By applying confocal imaging workflow

…In many cases the RNA binding protein TDP-43 aggregates in the cytoplasm leading to the loss of its nuclear functions, including as a splicing repressor. This results in the erroneous inclusion of intronic sequences known as cryptic exons (CEs) in several mature mRNAs. Recently, it has been shown that TDP-43 depletion leads to CE inclusion in UNC13A, which encodes a protein crucial for priming synaptic vesicles for release. The UNC13A

…an essential RNA/DNA binding protein, TDP-43. TDP-43 is a key constituent of neuronal ribonucleoprotein (RNP) granules involved in post-transcriptional mRNA regulation, including splicing, mRNA localization and translation of transcripts important for synaptic and axonal maintenance. We and others have previously shown that ALS-linked TDP-43 mutations in the LCD impair axonal transport of RNP granules. Specifically, we found that mutations in the conserved helical segment and flanking r

…condensation properties of TDP-43 specify its RNA binding and regulatory repertoire (Hallegger et al., 2021)

Axons degenerate before the neuronal soma in many neurodegenerative diseases. Programmed axon death (Wallerian degeneration) is a widely-occurring mechanism of axon loss that is well understood and preventable in animals. Its aberrant activation by mutation of the pro-survival gene Nmnat2 directly causes axonopathy in mice with severity ranging from mild polyneuropathy to perinatal lethality. Rare biallelic mutations in the homologous human gene cause related phenotypes in patients. NMNAT2 is a negative regulator of the prodegenerative NADase SARM1. Constitutive activation of SARM1 is cytotoxi