👤 Ebe Schiavo

The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i Show less

Exercise has been shown to support brain health, cognitive function, and increase levels of brain-derived neurotrophic factor (BDNF). While BDNF is known to support the central nervous system through improved brain metabolism, vasculature, neurotransmission and synaptic plasticity, the association between exercise-induced changes in BDNF concentrations and exercise-related cognitive improvements is still unclear. This study investigated the relationship between exercise-induced changes in plasma BDNF (pBDNF) and serum BDNF (sBDNF), and haemodynamic indicators of prefrontal cortex function in sedentary adults. Participants (n = 23, female = 7) were randomized into intervention (12-week cycling programme) and control groups (no intervention). Participants completed V̇O Show less

Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play crucial roles in neuronal development, synaptic transmission, and neuroplasticity. Deficits in BDNF/TrkB signalling and trafficking have been identified in several neurodegenerative diseases, including Alzheimer's disease (AD). Individuals with Down syndrome (DS) are at an increased risk of developing AD compared to the general population. Basal forebrain neurons (BFNs) are among the first to degenerate in AD and DS, but the mechanisms underlying their vulnerability remain unclear. Using BFNs derived from the Dp1Tyb mouse model of DS, we investigated neurotrophic signalling and trafficking deficits in AD-DS. We found enlarged early endosomes and elevated levels of active Rab5, a GTPase critical for early endosome formation, in Dp1Tyb BFNs. These abnormalities were associated with impaired transport of internalised TrkB from axon terminals to the soma. Using microfluidic devices, we demonstrated that axonal BDNF stimulation enhanced signalling endosome dynamics in wild-type but not Dp1Tyb BFNs, which is likely due to impaired axonal ERK1/2 signalling. Our findings establish a link between Rab5 hyperactivation, endosomal dysfunction, and impaired ERK1/2 signalling, highlighting the interplay between trafficking and neurotrophic signalling, and underscore the importance of targeting endolysosomal and signalling pathways to mitigate neuronal dysfunction in AD-DS. Show less

Myasthenia gravis (MG) is a disorder of the neuromuscular junction, typically associated with autoantibodies (Abs) that impair neuromuscular transmission. However, approximately 10% of cases are seronegative. Emerging evidence suggests that seronegative MG (SNMG) may be mimicked by hereditary conditions, particularly congenital myasthenic syndromes (CMSs), which require different treatments. In this study, we aimed to determine the proportion of CMS among patients diagnosed with SNMG. We used whole-exome sequencing (WES) in adult patients (aged ≥18 years) diagnosed with SNMG who were enrolled at 3 Austrian tertiary neuromuscular centers between August 2022 and January 2024. Genetic testing was conducted in individuals who remained seronegative after comprehensive serologic testing to exclude Abs against (clustered) acetylcholine receptors, muscle-specific kinase, lipoprotein receptor-related protein 4, and voltage-gated calcium channels. Moreover, we aimed to analyze clinical and demographic factors associated with the likelihood of receiving a molecular diagnosis. A total of 50 patients with SNMG (35 [70%] female) were referred for exome-based genetic screening. The median age at disease onset was 35 years (interquartile range 24.0-46.0 years). Seven patients (14%) were genetically diagnosed with CMS through WES (4 with Our findings provide evidence that a considerable proportion of patients diagnosed with SNMG have an underlying hereditary etiology. Notably, a (subjective) response to immunotherapies does not exclude a molecular CMS diagnosis. In conclusion, offering genetic testing to seronegative patients with myasthenic syndromes may have profound therapeutic implications. Show less

Combining different approaches (resequencing of portions of 54 obesity candidate genes, literature mining for pig markers associated with fat deposition or related traits in 77 genes, and in silico mining of porcine expressed sequence tags and other sequences available in databases), we identified and analyzed 736 SNP within candidate genes to identify markers associated with back fat thickness (BFT) in Italian Large White sows. Animals were chosen using a selective genotyping approach according to their EBV for BFT (276 with most negative and 279 with most positive EBV) within a population of ≈ 12,000 pigs. Association analysis between the SNP and BFT has been carried out using the MAX test proposed for case-control studies. The designed assays were successful for 656 SNP: 370 were excluded (low call rate or minor allele frequency <5%), whereas the remaining 286 in 212 genes were taken for subsequent analyses, among which 64 showed a P(nominal) value <0.1. To deal with the multiple testing problem in a candidate gene approach, we applied the proportion of false positives (PFP) method. Thirty-eight SNP were significant (P(PFP) < 0.20). The most significant SNP was the IGF2 intron3-g.3072G>A polymorphism (P(nominal) < 1.0E-50). The second most significant SNP was the MC4R c.1426A>G polymorphism (P(nominal) = 8.0E-05). The third top SNP (P(nominal) = 6.2E-04) was the intronic TBC1D1 g.219G>A polymorphic site, in agreement with our previous results obtained in an independent study. The list of significant markers also included SNP in additional genes (ABHD16A, ABHD5, ACP2, ALMS1, APOA2, ATP1A2, CALR, COL14A1, CTSF, DARS, DECR1, ENPP1, ESR1, GH1, GHRL, GNMT, IKBKB, JAK3, MTTP, NFKBIA, NT5E, PLAT, PPARG, PPP2R5D, PRLR, RRAGD, RFC2, SDHD, SERPINF1, UBE2H, VCAM1, and WAT). Functional relationships between genes were obtained using the Ingenuity Pathway Analysis (IPA) Knowledge Base. The top scoring pathway included 19 genes with a P(nominal) < 0.1, 2 of which (IKBKB and NFKBIA) are involved in the hypothalamic IKKβ/NFκB program that could represent a key axis to affect fat deposition traits in pigs. These results represent a starting point to plan marker-assisted selection in Italian Large White nuclei for BFT. Because of similarities between humans and pigs, this study might also provide useful clues to investigate genetic factors affecting human obesity. Show less

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75(NTR)), but the mechanism of receptor activation has remained elusive. Here, we show that p75(NTR) forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys(257) in its transmembrane domain. Mutation of Cys(257) abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75(NTR)/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75(NTR). FRET experiments revealed a close association of p75(NTR) intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys(257) did not alter the oligomeric state of p75(NTR), the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75(NTR) by a mechanism involving rearrangement of disulphide-linked receptor subunits. Show less