A5061515659- Hereditary Neurological Disorders
- Endoplasmic Reticulum Stress and Disease
- Nerve injury and regeneration
- RNA regulation and disease
- Genetic Neurodegenerative Diseases
- Signaling Pathways in Disease
- Neurological diseases and metabolism
- RNA Research and Splicing
- Peripheral Neuropathies and Disorders
- Neurogenetic and Muscular Disorders Research
- Cellular Mechanics and Interactions
- Muscle Physiology and Disorders
- Neurogenesis and neuroplasticity mechanisms
- Pharmacological Effects of Natural Compounds
- Amyotrophic Lateral Sclerosis Research
- Mitochondrial Function and Pathology
- Axon Guidance and Neuronal Signaling
- Autophagy in Disease and Therapy
- Botulinum Toxin and Related Neurological Disorders
- Peroxisome Proliferator-Activated Receptors
- Neurofibromatosis and Schwannoma Cases
- Pain Mechanisms and Treatments
- Regulation of Appetite and Obesity
- TGF-β signaling in diseases
- RNA modifications and cancer
IRCCS Ospedale San Raffaele
2006-2024
Vita-Salute San Raffaele University
2015-2021
Istituti di Ricovero e Cura a Carattere Scientifico
2015-2019
Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele
2015-2019
San Raffaele University of Rome
1999-2018
University College London
2003-2006
Environment Park
2003
University of Wisconsin–Madison
1999-2001
University of Würzburg
2001
Rockefeller University
2000
Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of holophosphatase), small molecule that safely and selectively inhibited regulatory subunit phosphatase 1 in vivo. bound the stress-induced PPP1R15A, but not related constitutive PPP1R15B, to prolong benefit an adaptive phospho-signaling pathway, protecting cells from otherwise...
The transcription factor Krox-20 controls Schwann cell myelination. cells in null mice fail to myelinate, and unlike myelinating cells, continue proliferate are susceptible death. We find that enforced expression cell-autonomously inactivates the proliferative response of major axonal mitogen β–neuregulin-1 death TGFβ or serum deprivation. Even 3T3 fibroblasts, not only blocks proliferation but also activates myelin genes periaxin protein zero, showing properties common with master...
Normal peripheral nerve myelination depends on Schwann cell-basal lamina interactions. An important component of cell basal is laminin--predominantly laminins 2 and 4. Mutations in the alpha chain common to these two isoforms are associated with dysmyelination mouse (dy) man (congenital muscular dystrophy). Thus, laminin 4 receptors also likely be for myelin formation. Several 2/4 detected at surface myelin-forming cells, namely, 6 beta 1 integrins dystroglycan. The evidence linking...
P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy humans, and a very similar demyelinating transgenic mice. retained the endoplasmic reticulum cells, where it promotes unfolded protein stress elicits response (UPR) associated with translational attenuation. Ablation Chop, UPR mediator, from S63del mice completely rescues their motor deficit reduces active demyelination by half. Here,...
Abstract Mitochondrial fission and fusion are essential processes in the maintenance of skeletal muscle function. The contribution these to development has not been properly investigated vivo because early lethality models generated so far. To define role mitochondrial repair, we have a transgenic mouse line that overexpresses fission-inducing protein Drp1 specifically muscle. These mice displayed drastic impairment postnatal growth, with reorganisation network reduction mtDNA quantity,...
Correct myelination is crucial for the function of peripheral nervous system. Both positive and negative regulators within axon Schwann cell to ensure correct onset progression during both development following nerve injury repair. The Sox2 transcription factor well known its roles in maintenance progenitor stem populations, but has also been proposed vitro as a regulator cells. We wished test fully whether regulates vivo show here that sustained expression blocks nerves maintains cells...
We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, protein zero (Mpz). Transgenic mice containing extra copies Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested and impaired sorting axons by Schwann cells. Myelination was restored breeding transgene into Mpz-null background, demonstrating dysmyelination does not result structural alteration or...
Missense mutations in 22 genes account for one-quarter of Charcot–Marie–Tooth (CMT) hereditary neuropathies. Myelin Protein Zero ( MPZ , P0 ) produce phenotypes ranging from adult demyelinating (CMT1B) to early onset [Déjérine-Sottas syndrome (DSS) or congenital hypomyelination] predominantly axonal neuropathy, suggesting gain function mechanisms. To test this directly, we produced mice which either the Mpz S63C S63del transgene was inserted randomly, so that endogenous alleles could...
To determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate unfolded protein Response (UPR).CMT1B is caused by >200 heterozygous in MPZ, major peripheral nerve myelin. Mutations Ser63del Arg98Cys mutant to be retained ER generally adaptive UPR. Treatments modulate UPR activation have improved cellular rodent models CMT1B raising possibility other would also respond favorably similar treatment. The unknown.We developed a dual luciferase...
Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, mutations in zero (MPZ) are two most common forms demyelinating CMT (CMT1), no treatments available for either. Prior studies MpzSer63del mouse model CMT1B have demonstrated that misfolding, endoplasmic reticulum (ER) retention activation unfolded response (UPR) contributed to neuropathy. Heterozygous patients with an arginine cysteine mutation MPZ (MPZR98C) develop...
Abstract To elucidate the molecular mechanisms involved in Schwann cell development, we profiled gene expression developing and injured rat sciatic nerve. The genes that showed significant changes dedifferentiated nerve were validated with RT‐PCR, situ hybridisation, Western blot immunofluorescence. A comprehensive approach to annotating micro‐array probes their associated transcripts was performed using Biopendium™, a database of sequence structural annotation. This significantly increased...
During development, Schwann cell numbers are precisely adjusted to match the number of axons. It is essentially unknown which growth factors or receptors carry out this important control in vivo . Here, we tested whether type II transforming factor (TGF) β receptor has a role process. We generated conditional knock-out mouse TGFβ specifically ablated only cells. Inactivation receptor, evident at least from embryonic day 18, resulted suppressed death normally developing and injured nerves....
Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss the phospholipid phosphatase consistently causes decreased PtdIns(3,5)P2 levels, cell-specific sensitivity to partial function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive characterized by severe demyelination axonal in human, both motor sensory involvement. However, it unclear whether has cell...
The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical mechanism for Schwann cell (SC)–axon interaction. Using mouse genetics, ablation the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) adult SCs severely affected paranodal nodal integrity led demyelination/remyelination. Expression levels HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied...
Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate myelination. Here we ask if modulating NRG1 levels in neurons would restore myelination a model congenital hypomyelinating neuropathy (CHN). Using mouse CHN, improved defects by early overexpression III. Surprisingly, improvement was...
Schwann cell differentiation and myelination in the PNS are result of fine-tuning positive negative transcriptional regulators. As starts, regulators downregulated, whereas ones upregulated. Fully differentiated cells maintain an extraordinary plasticity can transdifferentiate into “repair” after nerve injury. Reactivation is essential to generate repair cells. Negative have also been implicated demyelinating neuropathies, although their role disease remains elusive. Here, we used a mouse...
Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives nerve myelination by activating downstream signaling pathways such as PI3K/Akt MAPK/Erk converge on master transcriptional regulators myelin genes, Krox20. We reasoned modulating Nrg1TIII activity may constitute general therapeutic strategy to treat CMTs characterized...
Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive inducible expression mutant AR performed biochemical, histological functional analyses phenotype. show that polyQ-expanded causes dysfunction, premature death, IIb-to-IIa/IIx fiber-type change,...
Abstract P 0 glycoprotein, the most abundant protein in peripheral nerve, is expressed specifically Schwann cell lineage. Upstream of rat gene 1.1 kb DNA can activate expression cDNAs cells transgenic mice. However, promoter‐based transgenes has been inconsistent. As much as 9 5′ flanking sequence fused to lacZ never yielded detectable levels β‐galactosidase multiple lines We describe mice that express using complete mouse gene, including 6 sequence, all exons and introns, natural...