A5051545186- Cellular transport and secretion
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Peptidase Inhibition and Analysis
- Alzheimer's disease research and treatments
- Nerve injury and regeneration
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Parkinson's Disease Mechanisms and Treatments
- Neurogenesis and neuroplasticity mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Neurological disorders and treatments
- Protein Structure and Dynamics
- Neuroscience and Neuropharmacology Research
- Neuroscience and Neural Engineering
- Parathyroid Disorders and Treatments
- Cellular Mechanics and Interactions
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Signaling Pathways in Disease
- Computational Drug Discovery Methods
- EEG and Brain-Computer Interfaces
- Lysosomal Storage Disorders Research
- Skin and Cellular Biology Research
- Vitamin C and Antioxidants Research
- Protein Degradation and Inhibitors
- Neuroinflammation and Neurodegeneration Mechanisms
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto
2016-2024
Instituto de Biologia Molecular e Celular
2004-2023
Universidade do Porto
2004-2022
In the adult central nervous system, axonal regeneration is abortive. Regulators of microtubule dynamics have emerged as attractive targets to promote growth following injury organization pivotal for cone formation. this study, we used conditioned neurons with high regenerative capacity further dissect cytoskeletal mechanisms that might be involved in gain intrinsic axon capacity. Following a phospho-site broad signaling pathway screen, found capacity, decreased glycogen synthase kinase 3β...
Transthyretin (TTR) is a plasma homotetrameric protein that acts physiologically as transporter of thyroxine (T4) and retinol, in the latter case through binding to retinol-binding (RBP). A fraction TTR carried high density lipoproteins by apolipoprotein AI (apoA-I). We further investigated nature TTR-apoA-I interaction found from different sources (recombinant plasmatic) able process proteolytically apoA-I, cleaving its C terminus after Phe-225. TTR-mediated proteolysis was inhibited serine...
A fraction of plasma transthyretin (TTR) circulates in HDL through binding to apolipoprotein A-I (apoA-I). Moreover, TTR is able cleave the C terminus lipid-free apoA-I. In this study, we addressed relevance apoA-I cleavage by lipoprotein metabolism and formation amyloid fibrils. We determined that may also lipidated apoA-I, with being more effective lipid-poor prebeta-HDL subpopulation. Upon cleavage, discoidal particles displayed a reduced capacity promote cholesterol efflux from...
After trauma, regeneration of adult CNS axons is abortive, causing devastating neurologic deficits. Despite progress in rehabilitative care, there no effective treatment that stimulates axonal growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin 1 (Pfn1) as a coordinator actin microtubules (MTs), powering regeneration. In cones, Pfn1 increased retrograde flow, MT speed, invasion filopodia MTs,...
Abstract Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic is linked cognitive deficits LBD. Here, we investigated pathological impact αSyn on hippocampal neurons. We report that either overexpression or pre-formed fibrils (PFFs) treatment triggers formation cofilin-actin rods, synapse disruptors, cultured neurons synucleinopathy mouse models LBD patients. In vivo,...
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the intracellular deposition of Tau protein and extracellular amyloid-β peptide (Aβ). AD also neuroinflammation synapse loss, among others. The S100 family group calcium-binding proteins with intra- functions, that are important modulators inflammatory responses. S100B, which upregulated in patients most abundant member this family, was shown to inhibit vitro aggregation toxicity Aβ42, acting as neuroprotective...
TTR (transthyretin) was found recently to possess proteolytic competency besides its well-known transport capabilities. It described as a cryptic serine peptidase cleaving multiple natural substrates (including β-amyloid and apolipoprotein A-I) involved in diseases such Alzheimer's disease atherosclerosis. In the present study, we aimed elucidate catalytic machinery of TTR. All attempts identify residue were unsuccessful. However, metal chelators abolished activity. Proteolytic inhibition by...
Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a protease, cleaving apoA-I (apolipoprotein A-I) after phenylalanine residue. In present study, we further investigated substrate specificity. By using both P-diverse libraries library phosphonate inhibitors, preference for lysine residue in P1 was determined, suggesting that might have dual specificity that, addition to apoA-I, other substrates exist. Previous studies revealed involved...
To better understand the role of neuropeptide Y (NPY) in bone homeostasis, as its function regulation mass is unclear, we assessed expression this tissue. By immunohistochemistry, demonstrated, both at embryonic stages and adult, that NPY synthesized by osteoblasts, osteocytes, chondrocytes. Moreover, peptidylglycine alpha-amidating monooxygenase, enzyme responsible for activation amidation, was also expressed these cell types. Using transthyretin (TTR) KO mice a model augmented levels,...
Transthyretin (TTR) has a well-established role in neuroprotection Alzheimer's Disease (AD). We have setup drug discovery program of small-molecule compounds that act as chaperones enhancing TTR/Amyloid-beta peptide (Aβ) interactions. A combination computational repurposing approaches and vitro biological assays resulted set molecules which were then screened with our in-house validated high-throughput screening ternary test. prioritized list was obtained corroborated ITC studies....
In Krabbe's disease, a demyelinating disorder, add-on strategies targeting the peripheral nervous system (PNS) are needed, as it is not corrected by bone-marrow (BM) transplantation. To circumvent this limitation of BM transplantation, we assessed whether i.v. delivery immortalized EGFP(+) BM-derived murine mesenchymal stromal cells (BM-MSC(TERT-EGFP) ) targets PNS disease model, Twitcher mouse. vitro, BM-MSC(TERT-EGFP) retained phenotype primary BM-MSC and did originate tumors upon...
Mammalian CLASP1 and -2 are microtubule plus-end tracking proteins that selectively stabilize microtubules at the edge of cells promote nucleation growth Golgi, thereby sustaining cell polarity.In vitro analysis has shown CLASPs promoting factors. To date, a single isoform (called CLASP1 been described, whereas three CLASP2 isoforms known (CLASP2, -, - Although CLASP2/ enriched in neurons, suggesting isoform-specific functions, it proposed during neurite outgrowth act redundant...
Transthyretin Amyloid Polyneuropathy (ATTR-PN) is characterized by the deposition of amyloidogenic TTR, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting sensory axonopathy. Here, we investigated role cytoskeleton alterations axons from an ATTR-PN mouse model searched for genetic modifiers human patient samples. We employed hTTRA97S knock-in to examine cellular molecular changes axons. Our approach combined proteomic analysis sural nerve, live imaging...
Krabbe's disease (KD) is a demyelinating disorder caused by the deficiency of lysosomal galactocerebrosidase (GALC), affecting both central (CNS) and peripheral nervous system (PNS). A current therapy, hematopoietic stem cell transplantation (HSCT), ineffective at correcting PNS pathology. We have previously shown that systemic delivery immortalized bone marrow-derived murine mesenchymal stromal cells (BM-MSCs) diminishes neuropathology transplanted Twitcher mice, model KD. In this study, to...
Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth organelle transport in sensory neurons. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for segregation of functional compartments axonal outgrowth. Herein, we investigated whether TTR promotes elongation by modulating MT dynamics. We found that KO mice have an intrinsic increase dynamic MTs reduced levels acetylated α-tubulin peripheral axons. In addition, they failed to...