INHIBITORY EFFECT OF ANTI-GANGLIOSIDE ANTIBODIES ASSOCIATED WITH HUMAN NEUROPATHIES ON PERIPHERAL NERVE REPAIR
Guillain Barré syndrome (GBS) is an acute polyneuropathy characterized by the presence of ascending muscular paralysis and areflexia. At present the pathogenic mechanisms have not been fully elucidated, but it is assumed that paralysis in patients with axonal forms of GBS would be related to the development of a humoral autoimmune response against gangliosides, which is generated in response to antigenic determinants with structural homology to gangliosides present in the wall of agents causing gastrointestinal or respiratory infections that commonly precede the onset of clinical symptoms. Although the disease has a spontaneous resolution, a large number of patients presents an incomplete clinical recovery. In most cases, the degree of residual injury is associated with the extent and location of axonal damage present in these patients. It has also been observed that the presence of high titers of anti-ganglioside antibodies is associated with a slower and/or incomplete clinical recovery. On the other hand, it has been shown that the passive transfer of anti-ganglioside antibodies is capable of inhibiting the regenerative capacity of the Peripheral Nervous System in an animal model of axonal regeneration, confirming the relationship between the presence of anti-ganglioside antibodies and a poor prognosis in patients with GBS. Our laboratory aims to study the molecular basis of the inhibition on axonal regeneration mediated by anti-ganglioside antibodies, emphasizing the study of the effect of antibodies on the mechanism of axonal regeneration and peripheral nerve repair. These studies, by clarifying the pathogenic role of anti-ganglioside antibodies in GBS, could have a great impact on therapeutic management as well as providing knowledge for the development of new therapeutic strategies in GBS.
NEURONAL PROTECTION MECHANISMS DERIVED FROM THE AXON-MYELIN INTERACTION. ROLE OF MYELIN-ASSOCIATED GLYCOPROTEIN (MAG)
It has been demonstrated that the myelination process has a stabilizing role on the axons it ensheats, which suggests an intense molecular communication between the axonal membrane and the innermost myelin layer. One of the main components of myelin that mediates these effects is MAG, a minor glycoprotein of the Nervous System whose exclusive periaxonal expression appears associated with the beginning of the myelination process. On the other hand, our work group demonstrated new protective roles of MAG on neurons: modulation of neurodevelopment at an early postnatal stage and recently we have observed that the activation of MAG in myelinating cells contributes to the regulation of glutamate levels, the main excitatory neurotransmitter which, in high concentrations, it is toxic to resident cells of the central nervous system. These findings highlight the impact of axon-myelin communication on the homeostasis of the nervous system.
Our laboratory aims to study the molecular bases of the stabilizing and protective role exerted by myelin, by studying the physiological relevance of the interaction between MAG and its axonal receptors. These studies, in addition to clarifying the importance of the axon-myelin interaction in axonal stability and neuronal survival, could contribute to the development of new neuroprotective therapies to mitigate the devastating consequences on the quality of life observed in neurodegenerative pathologies such as Stroke and Multiple Sclerosis..
ROLE OF AUTOANTIBODIES AGAINST MYELIN COMPONENTS IN THE DEVELOPMENT AUTISTIC SPECTRUM DISORDERS
The advent of the new century brought great challenges in terms of medical research, and one of them consists of deciphering the possible causes that lead to the development of autism spectrum disorders (ASD), what we commonly call autism. Autism is considered a developmental disorder characterized mainly by alterations in the development of language, social interaction with peers and the presence of repetitive movements called stereotypes, as well as the presence of rigid behaviors that are currently detected before the age of 3 years. With an incidence of around 1/56 according to the latest report from the United States Center for Disease Control and Prevention, ASD is currently considered a new childhood epidemic if we take into account the increase in its incidence throughout the last 40 years. Among the possible causes associated with the development of ASD, factors as diverse as environmental toxins, changes in feeding habits that impact the intestinal microbial flora, have been proposed among others; all these always within a context of genetic susceptibility. In relation to possible autoimmune causes, several groups have observed the presence of varied autoimmune diseases not necessarily related to the nervous system (for example, celiac disease) among the direct relatives of a clinical subgroup of patients with ASD. In the hunt for a possible marker of auto-aggression of the immune system, several laboratories have demonstrated in these patients the presence in blood of proteins called antibodies that mistakenly recognize their own proteins such as components of myelin.
On the other hand, our laboratory has been interested in studying the mechanisms at the molecular level by which myelin is able to influence the survival of neurons during the early development of the nervous system. As part of this work, we have initially discovered that at early postnatal stage, myelin plays a critical role in the survival of a population of neurons responsible for the voluntary movement of our body. Furthermore, we have recently observed that genetically modified mice lacking a myelin component display alterations in the development of brain structures during the early postnatal stage, also affected in ASD. All this led us to hypothesize that the presence of antibodies that recognize myelin components in patients with ASD, indirectly exert a negative effect on neurons that translates into alterations in neuronal development associated with clinical symptoms of autism. To demonstrate our hypothesis at an experimental level, we have developed a model by which, after birth, we inject myelin-recognizing antibodies into rodents to simulate what happens in patients, then perform during the first 21 days of life (similar to the first 3 years life in humans) different studies capable of determining the clinical symptoms of autism. Surprisingly, we observed that rodents show a lower capacity for oral communication (obtained by recording their conversations developed at frequencies not audible to humans) and display alterations in their social and stereotyped behaviors. These behavioral alterations were associated with the alteration of the development of brain structures also affected in ASD, which allows us to think that the presence of antibodies that recognize myelin in patients has a causal role in the development of clinical symptoms. These findings generate new questions such as: What factor/s triggers the production of harmful antibodies in these patients? How can we clinically identify this subgroup of patients? Can injection of serum from patients reproduce symptoms in rodents? To solve these and other questions, our laboratory has developed a collaboration with the Institute of Child and Adolescent Neurology CETES from our city, which will allow us to study this subgroup of patients with a multidisciplinary perspective, with the hope that basic science can contribute knowledge that impacts the understanding of this enigma of modern medicine called Autism.
PEOPLE IN THE LAB
Biologist Bárbara Beatriz Baez
Student-PhD in Neuroscience-UNC
PhD Fellow from CONICET
PhD Fellow from CONICET
Biochemist Cristian Román Bacaglio
Student-PhD in Chemical Sciences-UNC
PhD Fellow from Foncyt
Biochemist Clara Nicole Castañeres
Student-PhD in Neuroscience-UNC.
PhD Fellow from CONICET.
FONCyT, UNC, MERCK, Mincyt Córdoba.
Publications (last 5 years)
M:J Virgolini; C. Feliziani; M.J. Cambiasso; P.H.H. Lopez & M.Bollo. Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside. BBA - Molecular Cell Research 2018. 2019; 1866(2):225-239.
A.J. Guimarães, M. Cerqueira, D.Zamith-Miranda, P.H.H. Lopez, M.L. Rodrigues, B.Pontes, at al. Host membrane glycosphingolipids and lipid microdomains facilitate Histoplasma capsulatum internalization by macrophages.Cellular Microbiology 2018. Cell Microbiol. 2019; 21(3):e12976.
Lopez PHH, Báez BB. Gangliosides in Axon Stability and Regeneration.
Prog Mol Biol Transl Sci. 2018;156:383-412.
Lopez PH, Aja S, Aoki K, Seldin MM, Lei X, Ronnett GV, Wong GW, Schnaar RL. Mice lacking sialyltransferase ST3Gal-II develop late onset obesity and insulin resistance. Glycobiology.2017 Jan;27(2):129-139.
Rozes Salvador V, Heredia F, Berardo A, Palandri A, Wojnacki J, Vivinetto AL, Shiekh KA, Caceres A and Lopez PHH. Anti-glycan antibodies halt axon regeneration in a model of Guillain Barrè Syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2.Exp Neurol. 2016; 278:42-53.
Palandri A, Rozes Salvador V, Wojnacki J, Vivinetto AL, Schnaar RL and Lopez PHH. Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75(NTR) receptor-mediated activation of RhoA signaling pathways. Cell Death Dis. 2015 ;6:e1876.
Lopez PH. Role of myelin-associated glycoprotein (siglec-4a) in the nervous system. Adv Neurobiol. 2014;9:245-62.