Welcome to the NeuroRepairLab
Pontificia Universidad Católica de Chile,
Faculty of Biological Sciences,
Department of Cellular & Molecular Biology
Our Work
VGF as a Mechanism of Brain Repair
The effects of exercise on health and preventing aging and disease are well described, but the molecular mechanisms of this regenerative process are unknown. Running activity has been described to trigger neurogenesis in the forebrain of mammals. However, it is not clear whether oligodendrogenesis can also be stimulated by exercise to reverse neuronal damage. Using a mouse model of progressive cerebellar ataxia induced by neuronal-specific deletion of the chromatin remodeler gene Snf2h, we have shown that running can significantly stimulate oligodendrogenesis in the ataxic brain (Alvarez-Saavedra et al, Cell Reports 2016). Interestingly, these experiments uncover the existence of an endogenous mechanism of brain repair and the molecular underpinnings highlight a robust upregulation of neuronal- and oligodendrocyte-specific neurotropic factors. We further isolated one of these factors, VGF (non-acronymic; unrelated to VEGF) and purified biologically-active peptides and its full-length form. One of these biologically-active peptides as well as the full-length form showed the ability to stimulate oligodendrogenesis and produce new myelin in vitro and in vivo, thereby mimicking the effects obtained by exercise. Thus, these findings provide a novel and clinically-relevant option to use VGF either as a peptide-based therapy (for example via intrathecal injections in ALS patients) or AAV-mediated delivery to the CNS to trigger myelination production and halt neuronal cell death. Hence, our work sheds important insight into the possibility of using oligodendrogenesis and myelin-associated mechanisms as novel therapeutic pathways to heal the brain.
Our lab strongly believes that new myelin synthesis may be able to stop or reverse the neurodegeneration observed in multiple pathologies. Therefore, we are currently investigating the use of the VGF growth factor as a therapeutic either in its natural form or as a synthetic agonist to provide healing to millions of patients worldwide suffering from incurable pathologies of the central or peripheral nervous systems. We are testing these hypotheses in multiple mouse models of disease.
Publications
Snf2h drives chromatin remodeling to prime upper layer cortical neuron development.
Front Mol Neurosci. (2019) Oct 17;12:243.
Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defects. Genes encoding epigenetic regulators are a frequent cause of intellectual disability and many have been shown to regulate progenitor cell growth, including our inactivation of the Smarca1 gene encoding Snf2l, which is one of two ISWI mammalian orthologs. Loss of the Snf2l protein resulted in dysregulation of Foxg1 and IPC proliferation leading to macrocephaly. Here we show that inactivation of the closely related Smarca5 gene encoding the Snf2h chromatin remodeler is necessary for embryonic IPC expansion and subsequent specification of callosal projection neurons. Telencephalon-specific Smarca5 cKO embryos have impaired cell cycle kinetics and increased cell death, resulting in fewer Tbr2+ and FoxG1+ IPCs by mid-neurogenesis. These deficits give rise to adult mice with a dramatic reduction in Satb2+ upper layer neurons, and partial agenesis of the corpus callosum. Mice survive into adulthood but molecularly display reduced expression of the clustered protocadherin genes that may further contribute to altered dendritic arborization and a hyperactive behavioral phenotype. Our studies provide novel insight into the developmental function of Snf2h-dependent chromatin remodeling processes during brain development.
Courses
BIO141C, BiologÃa De La Célula.
BIO351C, Biomedicina Celular Y Molecular.
BIO4103, Bases Celulares Y Moleculares De La Neurobiologia.
About the Principal Investigator
Assistant Professor
July 2017 - Present
Matias was born in Chile (1980) and received his Bachelor of Science in Molecular Biology at Montclair State University in New Jersey, USA (2005). He then returned to Chile and worked as Research Assistant at the Centro de Estudios Cientificos (www.cecs.cl) in Valdivia, Chile, where he investigated the reversibility of the Rett Syndrome phenotype using MeCP2 knockout and MeCP2 over-expressing mouse models (Alvarez-Saavedra et al, HMG 2007). Here, he also described a novel role for MeCP2 in cardiac development (Alvarez-Saavedra et al, HMG 2009). He then transitioned to Canada to complete his Master of Science in Biochemistry at the University of Ottawa with Dr. Hai-Ying Mary Cheng, where he investigated the role of microRNA-132 in the regulation of the circadian clock (Alvarez-Saavedra et al, HMG 2011). He then completed his Doctorate in Cellular & Molecular Medicine at the Ottawa Hospital Research Institute with Dr. David Picketts, where he described a key role for the Snf2h and Snf2l chromatin remodeling proteins in brain development and function (Alvarez-Saavedra et al, Nat Comm 2014). He then returned to the United States, under a Pew Latin American Fellows Postdoctoral Fellowship from the Pew Charitable Trusts, to work at the University of California, San Francisco with Dr. Michael McManus (2014-2015), and at the New York University Langone Medical Center/Howard Hughes Medical Institute with Dr. Danny Reinberg (2015-2017), where he worked on novel CRISPR technologies and the role of the nuclear matrix protein SATB2 in neuronal development. In mid-2017, he accepted a position in his homeland of Chile as Assistant Professor at the Department of Cellular & Molecular Biology at Pontificia Universidad Católica de Chile in Santiago, where his research focuses on three main themes: 1) VGF and its role in de novo myelination; 2) paraspeckle biology; and 3) A-to-I RNA editing as they relate to neuronal development and brain function. He is also the Founder & Acting Chief Executive Officer of Myelin Therapeutics, Inc. (www.myelintherapeutics.webs.com) where he leads the development of AAV-mediated gene therapies for the treatment of rare cerebellar disorders (New York, USA). At PUC, he teaches undergraduate and graduate courses in Cell Biology, Neurobiology and Molecular Genetics. In his spare time, Matias enjoys biking, trekking, swimming and playing with his dogs.