Montreal Neurological Institute
Montreal, Canada

The Montreal Neurological Institute and Hospital is an academic medical centre dedicated to neuroscience research, training and clinical care. The institute is part of McGill University and the hospital is one of the six teaching hospitals of the McGill University Health Centre. They occupy separate sections of the same buildings on McGill's downtown Montreal campus next to Molson Stadium. The institute and hospital are locally known as "The Neuro." Wikipedia.

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Dr. Brenda Milner in her office at the Montreal Neurological Institute and Hospital last month.

BOSTON--(BUSINESS WIRE)--Sync Project, Inc., a Boston-based company developing music as a personalized treatment across a range of conditions, is accelerating development of its physiologically-responsive music health platform. To date, Sync Project has raised $5 million in financing from investors Reid Hoffman, Greylock Partners (via Discovery Fund), Esther Dyson, David Shaw, Digital Garage, and PureTech Health. The company aims to validate interventions in both large-scale consumer experiments and controlled clinical studies in conditions such as stress, sleep, anxiety, and pain. “Developing music as precision medicine requires the right mix of people and funding that bridge consumer technology, music, and biotech,” said Marko Ahtisaari, CEO and Co-founder. “Our investors, advisors, and team are just such a mix. With the support of our investors, Sync Project is accelerating the development and validation of generative music for health.” “We are excited about the Sync Project team and how they are using artificial intelligence to create a new kind of personalized music that responds to your physiology to improve health,” said Reid Hoffman, partner at Greylock Partners. Sync Project is building a unique data set on the biometric impact (e.g., heart rate, brain activity, and sleep patterns) of certain structural properties of music (e.g., beat, key, and timbre). Datasets generated through Sync Project’s consumer initiatives will be further validated through controlled clinical trials in individuals suffering from sleep disorders, anxiety, and pain, among others. Sync Project aims to commercialize the clinical applications of this platform and deliver a personalized, low-cost, non-invasive therapy, across a range of conditions. Sync Project’s generative music platform is based on scientific research into the health effects of music. Recent research has shown that music can modulate neural systems like the dopamine response, autonomic nervous system, and other key pathways related to stress, movement, learning, and memory. This body of research shows that music affects some of the same neural pathways that are regulated by pharmaceuticals such as psychostimulants and suggests that music may hold significant therapeutic potential. Earlier this year, Sync Project launched, the first global experiment using algorithmically-generated music to potentially improve relaxation prior to sleep. Anyone with a smartphone can participate free of charge and contribute to a global data set on how music affects stress. Designed in collaboration with critically-acclaimed musicians, Sync Project’s generative music is personalized to an individual’s unique physiology. About Sync Project Sync Project is developing music as precision medicine. Sync Project’s generative music platform builds on scientific research into the health effects of music with a unique data set and machine learning that analyses musical attributes (like tempo and timbre) and their impacts on biometrics (like heart rate, brain activity, and sleep patterns.) Insights from Sync Project’s consumer initiatives will be further validated through controlled clinical trials in individuals suffering from sleep disorders, anxiety, and pain, among others. Sync Project aims to commercialize the clinical applications of their platform and deliver a personalized, low-cost, non-invasive therapy, across a range of conditions. Sync Project was co-founded by Marko Ahtisaari, Yadid Ayzenberg, Ketki Karanam, and PureTech Health (LSE: PRTC; Sync Project’s advisors and Board comprise a distinguished and diverse team of science, music, health and technology experts committed to uncovering the untapped potential of music’s ability to improve health: Robert Zatorre, Ph.D., Professor of Neurology and Neurosurgery at the Montreal Neurological Institute at McGill University; Adam Gazzaley, M.D., Ph.D., Director of the Neuroscience Imaging Center and Professor of Physiology, Psychology and Psychiatry at the University of California, San Francisco; Tristan Jehan, Ph.D., Founding Chief Technology Officer of The Echo Nest (Spotify); Peter Gabriel, six-time Grammy Award-winning British singer-songwriter; Annie Clark (St. Vincent), award-winning American singer-songwriter and multi-instrumentalist; Jon Hopkins, classically trained British pianist, critically acclaimed recording artist, Ivor Novello nominated composer of film scores, and prominent producer/collaborator; Esa-Pekka Salonen, Principal Conductor and Artistic Advisor of the Philharmonia Orchestra in London and Conductor Laureate for the Los Angeles Philharmonic; and Board Members Joi Ito, Director of the Massachusetts Institute of Technology Media Lab, Marjorie Scardino, DBE, FRSA, Chairman of the MacArthur Foundation, Board member of Twitter and former CEO of Pearson, Steven Holtzman, CEO of Decibel Therapeutics, and Daphne Zohar, Co-Founder and the Chief Executive Officer of PureTech Health. For more information visit or connect with us on Twitter @syncprojectco. Forward Looking Statement This press release contains statements that are or may be forward-looking statements, including statements that relate to the company's future prospects, developments and strategies. The forward-looking statements are based on current expectations and are subject to known and unknown risks and uncertainties that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks and uncertainties described in the risk factors included in the regulatory filings for PureTech Health plc. These forward-looking statements are based on assumptions regarding the present and future business strategies of the company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, neither the company nor any other party intends to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise.

Trempe J.-F.,Montreal Neurological Institute
Current Opinion in Structural Biology | Year: 2011

Polyubiquitin chains are assembled through the formation of an isopeptide bond between a lysine side-chain or terminal amino group of a proximal ubiquitin moiety and the carboxy-terminal of a distal ubiquitin moiety. Protein substrates tagged by polyubiquitin chains of different linkages undergo different fates. Many polyubiquitin chain types have been characterized so far, notably Lys11, Lys48, Lys63 and linear chains. These different types of chains are synthesized, disassembled and recognized by selective enzymes and receptors. Here I survey the structural basis for the selective binding of polyubiquitin chains of specific linkages, with an emphasis on recent advances in our understanding of polyubiquitin chain structure and functions. Recent work suggests linkage-type discrimination by members of the NF-κb signalling and DNA repair pathways and a specific role for Lys48-linked polyubiquitin chain recognition by proteasome-associated proteins. © 2011 Elsevier Ltd.

Dagher A.,Montreal Neurological Institute
Trends in Endocrinology and Metabolism | Year: 2012

Obesity is a neurobehavioral disorder that results from a combination of overeating and insufficient physical activity. Finely tuned mechanisms exist to match food intake to caloric expenditure. However, faced with abundant inexpensive and calorie-dense foods, many humans (and perhaps most) have a tendency to consume beyond their caloric needs. The brain controls food intake by sensing internal energy-balance signals and external cues of food availability, and by controlling feeding behavior; it is therefore at the centre of the obesity problem. This article reviews the recent use of functional brain imaging in humans to study the neural control of appetite, and how the neural systems involved may cause vulnerability to overeating in the obesogenic environment. © 2012 Elsevier Ltd.

Perucca P.,Montreal Neurological Institute | Gilliam F.G.,Geisinger Health System
The Lancet Neurology | Year: 2012

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects. © 2012 Elsevier Ltd.

Antonicka H.,Montreal Neurological Institute | Shoubridge E.A.,Montreal Neurological Institute
Cell Reports | Year: 2015

Cytoplasmic RNA granules play a central role in mRNA metabolism, but the importance of mitochondrial RNA granules remains relatively unexplored. We characterized their proteome and found that they contain a large toolbox of proteins dedicated to RNA metabolism. Investigation of four uncharacterized putative RNA-binding proteins-two RNA helicases, DHX30 and DDX28, and two proteins of the Fas-activated serine-threonine kinase (FASTKD) family, FASTKD2 and FASTKD5-demonstrated that both helicases and FASTKD2 are required formitochondrial ribosome biogenesis. RNA-sequencing (RNA-seq) analysis showed that DDX28 and FASTKD2 bound the 16S rRNA. FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. These data demonstrate that mitochondrial RNA granules are centers for posttranscriptional RNA processing and the biogenesis of mitochondrial ribosomes. © 2015 The Authors.

Bar-Or A.,Montreal Neurological Institute
Experimental Neurology | Year: 2014

Teriflunomide (Aubagio®) is a once-daily oral immunomodulatory disease modifying therapy (DMT) presently approved in several regions, including Europe, North America, Latin America and Australia, for the treatment of relapsing forms of multiple sclerosis (RMS; RRMS). The therapeutic mode of action of teriflunomide in MS continues to be investigated. This review summarizes the main efficacy and safety results of the clinical trial program leading to teriflunomide's approval, highlights a number of practical clinical considerations, and overviews its presumed therapeutic mode of action (MOA) based on pharmacokinetic and pharmacodynamic observations and the growing body of teriflunomide-related in vitro, pre-clinical (animal model), and in vivo human studies. © 2014 Elsevier Inc.

Durcan T.M.,Montreal Neurological Institute | Fon E.A.,Montreal Neurological Institute
Genes and Development | Year: 2015

Two Parkinson’s disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ubdependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKINmediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1– PARKIN pathway will be critical for our understanding of mitochondrial quality control. © 2015 Durcan and Fon.

La Piana R.,Montreal Neurological Institute
Archives of neurology | Year: 2012

To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing white matter disease. Case report. University teaching hospital. A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy. Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T(p.Ala87Val) and c.272G>A(p.Arg91His). To our knowledge,the latter missense mutation has never been previously reported. This is the second report of adult-onset vanishing white matter disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.

Twelve neurological disorders are caused by gene-specific CAG/CTG repeat expansions that are highly unstable upon transmission to offspring. This intergenerational repeat instability is clinically relevant since disease onset, progression and severity are associated with repeat size. Studies of model organisms revealed the involvement of some DNA replication and repair genes in the process of repeat instability, however, little is known about their role in patients. Here, we used an association study to search for genetic modifiers of (CAG)n instability in 137 parent-child transmissions in Machado-Joseph disease (MJD/SCA3). With the hypothesis that variants in genes involved in DNA replication, repair or recombination might alter the MJD CAG instability patterns, we screened 768 SNPs from 93 of these genes. We found a variant in ERCC6 (rs2228528) associated with an expansion bias of MJD alleles. When using a gene-gene interaction model, the allele combination G-A (rs4140804-rs2972388) of RPA3-CDK7 is also associated with MJD instability in a direction-dependent manner. Interestingly, the transcription-coupled repair factor ERCC6 (aka CSB), the single-strand binding protein RPA, and the CDK7 kinase part of the TFIIH transcription repair complex, have all been linked to transcription-coupled repair. This is the first study performed in patient samples to implicate specific modifiers of CAG instability in humans. In summary, we found variants in three transcription-coupled repair genes associated with the MJD mutation that points to distinct mechanisms of (CAG)n instability.

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