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Our reviews try to be the most accurate, precise and objective, like an observational study should be done.
We write here our own experiences with Dr. Gunvant Oswal's G-Therapy in the hope that someday, these will be useful for other needy people and give them the hope they need to face their disease.

THE DISCOVERY OF A “MASTER REGULATOR GENE” IN THE BRAIN

BY DR. PICKETTS – OTTAWA UNIVERSITY

15 years later Dr. Oswal's Hypothesis of a "Dormant supreme control" of the brain, researchers at the Ottawa University discovered a "Master Rugulator Gene" that can initiate recovery in damaged brains.

Researchers at The Ottawa Hospital and the University of Ottawa have discovered that a molecule triggered by running can help repair certain kinds of brain damage in animal models.

They found that this molecule, called VGF nerve growth factor inducible, helps to heal the protective coating that surrounds and insulates nerve fibres. Their study, published in Cell Reports, could pave the way for new treatments for multiple sclerosis and other neurodegenerative disorders that involve damaged nerve insulation.

“We are excited by this discovery and now plan to uncover the molecular pathway that is responsible for the observed benefits of VGF,” said Dr. Picketts, senior author of the paper and senior scientist at The Ottawa Hospital and professor at the University of Ottawa. “What is clear is that VGF is important to kick-start healing in damaged areas of the brain.”

The team made this discovery while studying mice genetically modified to have a small cerebellum, the part of the brain that controls balance and movement. These mice had trouble walking and lived only 25 to 40 days.

However, if these mice were given the opportunity to run freely on a wheel, they lived over 12 months, a more typical mouse lifespan. The running mice also gained more weight and acquired a better sense of balance compared to their sedentary siblings. However, they needed to keep exercising to maintain these benefits. If the running wheel was removed, their symptoms came back and they did not live as long.

Looking at their brains, the researchers found that the running mice gained significantly more insulation in their cerebellum compared to their sedentary siblings.

To find out why running was causing this insulation, the team looked for differences in gene expression between the running and sedentary mice and identified VGF as a prime candidate. VGF is one of the hundreds of molecules that muscles and the brain release into the body during exercise. It also has an anti-depressant effect that helps make exercise feel good.

When the research team used a non-replicating virus to introduce the VGF protein into the bloodstream of a sedentary mutant mouse, the effects were similar to having the mouse run – more insulation in the damaged area of the cerebellum, and fewer disease symptoms.

“We saw that the existing neurons became better insulated and more stable,” said Dr. Matías Alvarez-Saavedra, the lead author on the paper. “This means that the unhealthy neurons worked better and the previously damaged circuits in the brain became stronger and more functional.”

Dr. Alvarez-Saavedra obtained his PhD in Dr. Picketts’ research group, and is currently a postdoctoral fellow at the New York University School of Medicine and the Howard Hughes Medical Institute.

“We need to do broader research to see whether this molecule can also be helpful in treating multiple sclerosis and other neurodegenerative diseases,” said Dr. Picketts.

This study was funded by the Canadian Institutes of Health Research, with support from The Ottawa Hospital Foundation. The group has now received funding from the MS Society of Canada and the Canadian Partnership for Stroke Recovery to further investigate VGF. Dr. Picketts is also a member of the University of Ottawa Brain and Mind Research Institute. Dr. Alvarez-Saavedra is funded by a Pew Latin American Postdoctoral Fellowship in the Biomedical Sciences.

Full reference: Voluntary running triggers VGF-mediated oligodendrogenesis to prolong the lifespan of Snf2h-null ataxic mice. Matías Alvarez-Saavedra, Yves De Repentigny, Doo Yang, Ryan W. O’Meara, Keqin Yan, Lukas E. Hashem, Lemuel Racacho, lya Ioshikhes, Dennis E. Bulman, Robin J. Parks, Rashmi Kothary, and David J. Picketts. Cell Reports (2016), http://dx.doi.org/10.1016/j.celrep.2016.09.030. October 11, 2016.

Associated researches:

With another research fellow, Dr. Richard Gibbons they identified the ATRX gene as the cause of the ATR-X syndrome, a severe form of X-linked intellectual disability (XLID). They cloning of the ATRX gene established the paradigm that dysfunctional chromatin remodeling proteins cause human disease, specifically neurodevelopmental disorders. Dr. Picketts has extended his research to explore the role of three other chromatin-interacting proteins in disease and brain development including PHF6 and the ISWI proteins, SNF2H and SNF2L.

Intellectual Disability and Brain Development: Role of Epigenetic Regulators
Research in Dr. Picketts’ laboratory focuses on the role of chromatin remodeling proteins in neural development and intellectual disability disorders.

They utilize transgenic mouse models in which genes encoding epigenetic regulators are genetically inactivated to identify their requirement during brain development and to obtain insight into the mechanisms causing intellectual disability. Determining the genes and developmental pathways regulated by these epigenetic regulators is critical for the generation of novel therapeutics for patients.

Project Descriptions:

1. Defining the molecular role of ATRX
The involvement of chromatin remodeling proteins in human disease was established by their cloning of the ATRX gene as the cause of a severe X-linked intellectual disability (XLID) syndrome usually associated with alpha-thalassemia.

Recent excitement in the field came from the findings that ATRX in combination with DAXX loads the histone variant H3.3 onto telomeres and that ATRX recognizes G-quadruplex structures.

Their most recent work (Huh et al (2012) J. Clin. Invest. 122:4412-23) involved ATRX ablation in muscle. These mice have a regeneration deficit from an inability to activate satellite cell expansion that arises from stalled replication and telomere fragility.

They are currently investigating the role of ATRX in the resolution of G-quadruplexes, since the structures are prevalent at telomeres.

2. Mammalian ISWI proteins in brain development
The ISWI proteins, SNF2H and SNF2L have complementary expression patterns in the developing mouse brain. Snf2h is highly expressed in progenitors whereas Snf2l expression becomes more prevalent upon neuronal differentiation.

They have generated Snf2h and Snf2l mutant mice to investigate the role of these proteins in brain development. The loss of Snf2l results in mice with a larger brain due to increased proliferation of intermediate progenitor cells. In contrast, Snf2h cKO mice have a hypoplastic cerebellum due to poor proliferation of granule neuron progenitors. The expansion and differentiation of these progenitors is controlled by homeotic transcription factors, namely Foxg1 in the forebrain and En-1 in the cerebellum.

They are currently investigating the coordinate regulation of these genes by the ISWI proteins with the hypothesis that Snf2h is required for their activation to promote proliferation while Snf2l promotes their repression leading to differentiation.

Chromatin remodeling proteins and XLID:

Chromatin remodeling proteins play a dynamic role in the regulation of gene expression through the alteration of nucleosome structure (histone acetylation, phosphorylation and methylation) or the ATP dependent repositioning of nucleosomes (SWI/SNF complex, ISWI). Their involvement in genetic disease was established by their cloning of the ATRX gene, a novel SWI/SNF family member that is mutated in a severe X-linked intellectual disability syndrome usually associated with alpha thalassemia.

This paradigm has since been extended to include genes encoding almost every type of chromatin modifying protein (see Table 1).

They continue to study the role of these proteins in neural development to understand how they contribute to disease pathogenesis. Several current projects are described below.

1. ATRX function and the ATR-X syndrome:

They make use of multiple Cre drivers to conditionally inactivate Atrx (cKO) in mouse tissues involved in the human syndrome. They have made use of a muscle cKO to define a role for Atrx in replication and/or maintenance of heterochromatin. They identified a cell non-autonomous role for Atrx in the developing retina that affects the survival of inter-neurons. Finally, they are defining the role of Atrx in the developing forebrain. Each of these projects is ongoing and continues to provide fundamental knowledge on the global and cell type specific roles of Atrx.

2. Dual functions of the ISWI proteins SNF2H and SNF2L:

To extend their analysis of the role of chromatin remodeling proteins in neural development they have characterized the human and murine SNF2H and SNF2L genes. SNF2H is expressed in proliferating neuronal cell populations whereas SNF2L is expressed predominantly in differentiating and/or maturing neurons. Mice inactivated for SNF2L have enlarged brains due to enhanced proliferation whereas mice deficient for SNF2H have proliferative defects and underdeveloped brains. Current lab work aims to understand how these genes regulate common master neuronal developmental homeotic genes to control the size and patterning of specific brain structures.

For further information, you can visit http://www.ohri.ca/profile/PickettsLab

We are a group of parents that want to share their knowledge and their experiences with other parents of brain injured children.