Research Projects

16 researchers will share $1M in funding to pursue research on ARSACS. A total of 13 research projects have been selected by the Foundation for 2018-2019 with the goal of finding a treatment for ARSACS.

Integrated Validation Pipeline for Candidate Drugs for ARSACS- Dr. Bernard Brais

The aims of the project are to validate candidate compounds in neurons and to combine genomics and proteomics strategies to pinpoint pathways affected by candidate drugs.

Duration: One year
Grant : $80,000

Contact

Dr. Bernard Brais

Dr. Bernard Brais

Dr. Bernard Brais, co-director of the neuromuscular group of the Montreal Neurological Institute and Hospital
3801 University Street Montreal, Quebec, Canada H3A 2B4
Tel:(514)-398-3334; Email: bernard.brais@mcgill.ca

Elucidating Mechanisms Underlying Motor Coordination Rescue in a Mouse Model of ARSACS- Dr. Alanna Watt and Dr. Anne McKinney

Description
Aim 1 Elucidate mechanism underlying MitoQ rescue of motor coordination in Sacs-/- mice:
(i)test mitochondrial dynamics and morphology using Mito-tracker administered intracellularly in Purkinje cells in treated and untreated Sacs−/− mice, (ii) test mitochondrial function using assays for mitochondrial respiration and energy consumption, and (iii) determine whether MitoQ rescues the abnormal somatodendritic localization of phosphorylated neurofilament in Sacs−/− mice.In addition to understanding the mechanism by which MitoQ rescues motor behaviour, the work will continue with the Brais lab to understand how and if a drug recently identified by a drug screen they conducted with V151 improves Purkinje cell morphological and physiological deficits.

Aim 2 Identify mechanism(s) underlying Purkinje cell firing deficits in Sacs-/- mice.
Over the coming 2018/2019 year we expect to make substantial advances in understanding the following 5 questions:
(a) How does MitoQ lead to behavioral improvements in Sacs−/− mice?
(b) Does V151 rescue physiological abnormalities in Sacs−/− mice?
(c) Are glutamate transporters altered in Sacs−/− mouse cerebellum?
(d) Does rescue of firing rate directly ameliorate behavioral phenotype in Sacs−/− mice?
(e) Is zebrin neuroprotective in Sacs−/− mouse cerebellum?

Duration : One year
Grant: $125,000
Contacts:

Dr. Alanna Watt

Dr. Alanna Watt

Dr. Alanna Watt, Department of Biology McGill University Bellini Life Sciences Bldg.
3469 Sir William Osler, Montreal, Quebec Canada H3G 0B1 Office: Rm. 265 | Lab: Rm. 257
Tel: (514)-398-2806; Fax: (514)-398-5069; Email: alanna.watt@mcgill.ca

Dr. Anne McKinney

Dr. Anne McKinney

Dr. Anne McKinney, Department of Pharmacology and Therapeutics, McGill University Bellini Life Sciences Bldg
3469 Sir William Osler, Montreal, Quebec Canada H3G 0B1
Tel: (514)-398-5685; Fax: (514)-398-2045; Email: anne.mckinney@mcgill.ca

Phenotyping ARSACS in Vitro Using hiPSCs Reprogrammed from Patients and Differentiated into Motor Neurons and Schwabb cells – Dr. François Berthod

The objectives are to: (1) develop and characterize a 3D in vitro human model constituted of fibroblasts, motor
neurons, Schwann cells and myoblasts that recapitulate the ARSACS phenotype at the motor neuron scale, (2)
determine whether the ARSACS phenotype is homogeneous between different patients in vitro.

Duration: one year
Grant: $80,000

contact:
Dr. François Berthod, professor department of Surgery
Faculty of medicine of University Laval
tel: 418-990-8255 x61705; courriel: francois.berthod@fmed.ulaval.ca

Unbiased Sacsin Client Identification and Genetic Intervention in a Mouse Model of ARSACS- Dr. Stephen Strack

This research project utilizes Sacs KO mice to answer two fundamental questions:
1) Can we leverage recent advances in quantitative proteomics to uncover early biomarkers and perhaps drivers of ARSACS pathology in the cerebellum?
2) Can genetic modulation of the mitochondrial fission/fusion equilibrium counteract cerebellar symptoms and PC degeneration? Results from this research are expected to advance our understanding of ARSACS disease mechanisms and point to avenues for therapeutic intervention.

Duration: one year
Grant: $50,000

Contact :

Dr. Stefan Strack

Dr. Stefan Strack

Dr.Stefan Strack, Professor of Pharmacology University of Iowa Carver College of Medicine
2-452 BSB, 51 Newton Rd. Iowa City, IA 52242
Tel:(office/lab): (319)384-44[39/47]; Fax: (319) 335-8930
www.medicine.uiowa.edu/pharmacology/faculty/strack.html

Exploring Neuronal Roles for Sacsin: from Dendritic Spines to Neuronal Polarity- Dr. Bernard Brais

The focus will be on

Aim 1. The objective is to submit a paper that will elucidate the role of Sacsin and EndoB2 in dendritic spines that will include our BioID results.

Aim 2. We will explore if a neuronal polarity defect in cytoskeletal protein trafficking might also be an important aspect of
ARSACS pathophysiology.

Duration: One year
Grant $80,000

Contact

Dr. Bernard Brais

Dr. Bernard Brais

Dr. Bernard Brais, co-director of the neuromuscular group of the Montreal Neurological Institute and Hospital
3801 University Street Montreal, Quebec, Canada H3A 2B4
Tel:(514)-398-3334; Email: bernard.brais@mcgill.ca

Unravelling Progression Biomarkers in ARSACS: a Multicenter, Transmodal Combined Fluid Biomarker and Magnetic Resonance Imaging Study – Dr. Matthis Synofzik and Dr. Roberta La Piana

A combined transmodal fluid biomarker and neuroimaging study to unravel progression biomarkers for ARSACS, bringing together a unique transatlantic, multi-center consortium which will yield the by far largest , most comprehensive biomarker investigation in ARSACS worlwide, creating combined clinical, biomaterialand multimodal MRI data-sets from 125 ARSACS patients across continents. Fluid biomarker investigations will focus on neurofilaments (NFs), a particularly promissing blood biomarker candidate in ARSACS.

Duration: on year
Grant: $90,000 per year
Contacts:

Dr Matthis Synofzik, Dept. of Neurodegenerative Diseases Hertie-Institute for Clinical Brain Research
Hoppe-Seyler-Strasse 3 72076 Tübingen, Germany
Tel: 49(0)7071-2982060; Fax: 49 (0)7071-2925001; email: matthis.synofzik@uni-tuebingen.de


Dr Roberta La Piana , Montreal Neurological Institute, McGill University
Montreal, Quebec
email: roberta.lapiana@mail.mcgill.ca

Unravelling Co-Translational Quality Control of Mutant Sacsin in the ARSACS Pathogenesis – Dr. Francesca Maltecca

The main objectives of this research project are to:
(i) verify if a co-translational QC is the cause of sacsin absence in patients, thus uncovering the
earliest step in ARSACS pathogenesis;
(ii) ameliorate genotype-phenotype correlation in ARSACS by assaying residual amount of sacsin
levels in a panel of patient fibroblasts carrying different mutations.
The comprehension of the molecular mechanism underlying loss of mutant sacsin is crucial to
improve the knowledge on ARSACS pathogenesis.

Duration: One year
Grant : $40,000

Contact:

Dr. Francesca Maltecca

Dr. Francesca Maltecca

Dr. Francesca Maltecca, Universita Vita-Salute San Raffaele
Via Olgettina 60 20132 Milan, Italy
Tel:39 022643.9116; Fax: 39 022643.6352 ; Email: maltecca.francesca@hsr.it

Caractérisation du profil clinique de la clientèle pédiatrique atteinte de l’ARSACS- Dre Cynthia Gagnon

Les objectifs de ce projet sont de :
1. Documenter les atteintes motrices des membres inférieurs et supérieurs des enfants atteints
d’ARSACS en termes de coordination, endurance et vitesse de marche, force des mains et
sévérité de la maladie;
2. Déterminer la validité de construit des outils pour la clientèle pédiatrique atteinte d’ARSACS.
Méthode
Devis : Transversal multicentrique
Participants : Le recrutement se fera au sein des cohortes de patients suivis à la clinique des maladies
neuromusculaires de Saguenay, à l’Institut de réadaptation en déficience physique de Québec (IRDPQ)
et au centre de réadaptation Marie-Enfant de Montréal.

Duration: one year

Grant: $23,500

Contact:

Cynthia Gagnon

Cynthia Gagnon

Dre Cynthia Gagnon
1200 Jonquière, QC G7X 7X2
TEL: 1-418-695-7700 poste 2756; Fax: 1-418-695-7758; email: Cynthia.Gagnon4@USherbrooke.ca

Development of Optimized Molecules That Reverse The Molecular Phenotype of ARSACS – Dr. Michel Bouvier

The goal of this project is to develop small molecules that reverse the cellular phenotype of ARSACS into
a drug that would stop the progression of the disease and/or lead to clinical improvement. The project is
a multidisciplinary collaboration between Dr Bernard Brais’ (McGill Univ.) and Dr Michel Bouvier’s (IRIC,
Institute of Researcher in Immunology and Cancer, Univ. of Montreal) laboratories with the participation
of the High Throughput Screening (HTS) and Medicinal Chemistry core facilities at IRIC.

Duration: One year
Grant: $150,000

Contact

Dr.Michel Bouvier, Institute for Research in Immunology and Cancer (IRIC)
IRIC | Université de Montréal C.P. 6128, succursale Centre-ville, Montréal (Québec) H3C 3J7
Tel: (514)-343-6319 ; Email: michel.bouvier@umontreal.ca

Functional and Structural Studies of Sacsin Using Baculovirus Expression Systems- Dr. Kalle Gehring

The central goal is to obtain pure full-length sacsin in high enough concentration for
structural and functional assays. We also aim to express and study the interaction of large
multidomain fragments of sacsin. These will allow us to study the structure of sacsin by X-ray
crystallography and cryo-electron microscopy. Purified protein will also enable assays of sacsin
chaperone function and protein-protein interactions.

Duration: one year
Grant: $80,000

Contact:

Dr.Kalle Gehring Dept. of Biochemistry, McGill University
Life Science Complex, Room 469, 3649 Prom. Sir William Osler,Montreal QC, H3G 0B1
Tel: 514-398-7287; Email:kalle.gehring@mcgill.ca

Axonal Transport and Axonal Survival in ARSACS Mice- Dr. Thomas Schwarz

The goal of this project is to develop therapeutic interventions that would ameliorate the
degeneration of neurons in ARSACS.
Specific Aims.
1. Test compounds that enhance mitochondrial motility in rat hippocampal neurons to determine if they also
enhance motility in sacsin -/- mouse neurons.
2. Establish conditions for cultured sacsin-/- neurons that will provoke the formation of neurofilament
aggregates seen in vivo in older sacsin -/- mice and determine if those aggregates impeded proper
transport of mitochondria.
3. Test compounds that enhance mitochondrial motility to determine if they can restore normal levels of
mitochondrial transport in the presence of neurofilament aggregates.
4. Determine if the NMNAT/SARM pathway is involved in the degeneration and death of neurons in vivo in
sacsin -/- mice.

Duration: one year
Grant: $50,000
Contact:

Dr. Thomas L. Schwarz

Dr. Thomas L. Schwarz

Dr. Thomas L. Schwarz, Professor, F.M. Kirby Neurobiology Center Children’s Hospital, Boston Children’s Hospital CLSB12-130
Harvard Medical School CLSB 12-130, 3 Blackfan Street, Boston, MA 02115
Tel:(617)-919-2219 (office) or (717)-919-2271(fax)

High-throughput Screening of Small Molecule Libraries to Identify Novel Therapeutics for ARSACS Using Patient Cells – Dr. Paola Giunti and Dr. Suran Nethisinghe

This research consists of :
1. Establishing baseline measurements for our mitochondrial and cytoskeletal phenotypic readouts on
the Perkin Elmer Opera Phenix High Content Screening platform. We will use
tetramethylrhodamine methyl ester perchlorate (TMRM, a cationic fluorescent dye sequestered
by healthy mitochondria) to measure basal mitochondrial membrane potential (ΔYm) as a read
out of mitochondrial health in live cells. In parallel, fixed cells will be dual-stained by
immunofluorescence for Tom20 and vimentin to examine the mitochondrial network and
intermediate filament morphology, respectively. We will set out and optimise the parameters for
the screen using ARSACS patient and control fibroblast lines.

2. Performing small molecule library screens of Reata Pharmaceutical’s compound library and
BioAscent’s Phenotypic Toolbox.

3. Validating positive hits using traditional confocal, immunoblotting and luminescence assays. This
will include examining NADH levels and calcium signalling on a CCD camera (14, 15). Respiration
rate and oxygen consumption will be measured with a Clark-type oxygen electrode (16). These
studies will provide mechanistic insight into the mode of action of these compounds.

Duration: one year
Grant: $50,000

Contacts

Dr. Paola Giunti

Dr. Paola Giunti

Dr. Paola Giunti, Ataxia Centre, Department of Molecular Neuroscience
UCL Institute of Neurology, Queen Square House
Queen Square, London WC1N 3BG, United Kingdom
Tel: +44 (0)20 3448 3153;


Dr. Suran Nethisinghe, Ataxia Centre, Department of Molecular Neuroscience
UCL Institute of Neurology, Queen Square House
Queen Square, London WC1N 3BG, United Kingdom
Tel: +44 (0)20 3448 3153; email: S.Nethisinghe@ucl.ac.uk

Therapeutic Approaches for ARSACS- Dr. Benoit Gentil and Dr. Heather Durham

The current proposal proposes to capitalize on our discoveries and to move forward in two
directions. First, pursue the protein/gene replacement approach until it produces a preclinical proof of
concept that includes a translatable delivery method. Second, assess the therapeutic potential of HDAC
inhibitors for ARSACS. Although not included as a specific aim in this proposal, developments with
HSP inducers in the ALS study will be applied in the ARSACS models.

Duration: One year
Grant: $80,000

Contacts

DR. Benoit Gentil
Room 649, Montreal Neurological Institute
3801 University street, Montreal, H3A 2B4
Tel: 514-398-8509; Fax: 514-398-1509; email: benoit.gentil@mcgill.ca

Dr. Heather Durham
Room 649, Montreal Neurological Institute
3801 University street, Montreal, H3A 2B4
Tel: 514-398-8509; Fax: 514-398-1509; email: heather.durham@mcgill.ca