Research Projects

Twelve ARSACS research projects to receive $1M in funding in 2016-2017

This year again,  the Foundation is funding $1Million  on ARSACS research as part of its  mission. Researchers with different expertise will work together on the following twelve research projects contributing to the advancement of  research.  Note: the project descriptions  are not translated.

"Analyzing the influence of ARSACS mutations on the function of human neurons derived from induced pluripotent stem cells." – Dr. Peter McPherson and Dr. Edward Fon

The researchers will use genome editing of hiPSCs to test the hypothesis that point mutations in the SACS gene lead to alterations in mitochondrial function and neurofilament organization in neurons derived from ARSACS patients.
Specific aim 1: Generate genome-edited neurons from fibroblasts of ARSACS patients.
Specific aim 2: Examine the influence of sacsin mutations on the cell biological properties of human neurons.

Duration: 2nd year of the project
Grant: $100,000 per year
Contacts:

Dr Peter Mc Pherson

Dr Peter Mc Pherson

Dr. Peter McPherson,  Professor, Montreal Neurological Institute McGill Institute
Tel:(514)-398-7355; Email: peter.mcpherson@mcgill.ca

Dr. Edward Fon

Dr. Edward Fon

Dr. Edward Fon, Professor, Director McGill Parkinson Program
Montreal Neurological Institute, McGill Institute
Tel:(514)-398-8398; Email: ted.fon@mcgill.ca

" "Role of Neurofilaments in the Pathogenic Cascade of ARSACS" – Dr. Heather Durham

The research project has the following  specific objectives :

Aim 1. Determine the effect of sacsin domains

Aim 1.1:  Determine the effect of sacsin domains on IF architecture and IF bundling in ARSACS models.  Aim 1.2: Determine which domains in combination are essential to rescue the ARSACS phenotype.

Aim 2. Develop a peptide drug using neuroprotective sacsin domains. 

Aim 2.1: Optimize the therapeutic polypeptide sequence.

Aim 2.2: Verify intracellular delivery of Sacsin domain polypeptides.

Aim 2.3:  Investigate the dose-response of peptide efficacy in alleviating the phenotype in ARSACS culture models.

Aim 2.4:  Conduct a preliminary investigation of toxicity of Sacs.

 

Duration: one year
Grant: $100,000
Contact:

Dr Heather Durham

Dr Heather Durham

Dr. Heather Durham, professor McGill University
Tel:(514)-398-8509; Email: heather.durham@mcgill.ca

"The Role of Sacsin in Autophagy Offers Novel Therapeutic Opportunities"- Dr. Federica Morani

 

The specific aims of the research project are the following:
To investigate the role of sacsin in autophagy we will propose to answer the following questions:
1. Is autophagy defective in sacsin KD (knockdown) cells, such as SH-SY5Y or ARSACS skin fibroblasts? If yes, where is the stop in the autophagy process and how the autophagy flux operates?
2. Are CASA and mitophagy independent or co-dependent functional pathways in ARSACS? What are the

Dr. Federica Morani

Dr. Federica Morani

autophagy-related interactors of sacsin?
3. Can pharmacological or genetic induction/up-regulation of autophagy in sacsin KD cells/ skin fibroblasts from ARSACS patients rescue ARSACS phenotype (in terms of cell death/PC degeneration, mitochondrial dysfunction)?
Experimental

Duration: one year
Grant: $55,000
Contact:

Dr. Federica Morani, PhD, Neurogenetics and Molecular Medicine Laboratory, IRCCS Fondazione Stella Maris

Via dei Giacinti 2, 56128 Calambrone (PISA), Italy

Tel: (39)050-886238; Fax:(39)50-88247

Email: morani.federica@gmail.com

"Disrupted Protein Homeostasis in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay""- Dr. Paul Chapple

Dr. Paul Chapple

Dr. Paul Chapple

The objectives of the research project are to:

1. Identify the proteostasis systems that are activated in sacsin null cells

2. Identify proteins that are recruited to the aggresome-like structure in sacsin null cells

3. Identify if there is evidence for disruption of proteostasis systems in human ARSACS neurons.

 

 

 

 

Duration: Three years
Grant: 18,965 Pounds ($32,400CDN) per year
Contact:

Dr.Paul Chapple, Professor of Molecular Cell Biology
Centre for Endocrinology Barts and The London, Queen Mary’s School of Medicine and Dentistry
1st Floor North ,John Vane Science Building,Charterhouse Square
London, EC1M 6BQ
T: +44 (0) 20 7882 6242
E: j.p.chapple@qmul.ac.uk

 

"Caractérisation des déficiences, limitations d’activités et restrictions de participation ainsi que de leurs interrelations chez les personnes atteintes d’ataxie Charlevoix-Saguenay (ARSACS)"- Dr Luc Hébert

Caractériser les déficiences de force et de contrôle de mouvements volontaires et les limitations d’activité liées à la mobilité; 2) caractériser leurs interrelations; et 3) identifier les variables cliniques qui expliquent le mieux les limitations d’activités telle que la vitesse de marche.

Luc J. Hébert

Luc J. Hébert

 

Durée: un an
Bourse : $98,000

Contact:

Dr.Luc Hébert , Chercheur, CIRRIS,

Bureau H-1702 . IRDPQ, 525 boulevard Hamel, Québec QC  G1M 2S8

Téléphone: 418-529-9141 poste 6579

Rescuing mitochondrial division in ARSACS by CIDR"- Dr. Stefan Strack

Part II of the project

Aim 1. Generate and characterize mice with chemically inducible mitochondrial division in Purkinje neurons (L7-CIDR mice).

Aim 2. Evaluate rescue of Purkinje cell degeneration and motor deficits in SACS-/- mice by inducible mitochondrial division.

Duration: 2nd year of the project
Grant: $100,000 per year
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

"Sacsin Chaperone Activity" – Dr. Jason Young

The aims of the research project are:

1. Address Hsc70-dependent maintenance of NFH

2. Engineer Hsc70 to identify other sacsin-dependent Hsc70 substrates

Duration: one year
Grant: $42,363
Contact:

Dr. Jason Young

Dr. Jason Young

Dr. Jason Young, Associate Professor Department of Biochemistry
Francesco Bellini Life Sciences Building, 3649 promenade Sir-William-Osler, Office: Room 467; Lab: Room 457, Montreal, Quebec H3G 0B1
Tel:(514)398-2006; Lab: (514)398-5954 Fax:(514)398-7384 Email: ason.young2@mcgill.ca

"High-throughput strategy to identify large domains of Sacsin" – Dr Kalle Gehring

We propose two aims: systematic deletion analysis to identify domain boundaries within SIRPR1 and random mutagenesis to optimize proteins for crystallization. The information about sacsin protein domains will be used to advance the structural studies funded under the ARSACS Foundation/ CIHR New Emerging Team Grant.

Duration: one year
Grant: $98,280
Contact:

Dr Kalle Gehring

Dr Kalle Gehring

Dr. Kalle Gehring, Professor Department of Biochemistry MCGill University
Francesco Bellini Life Sciences Building, 3649 promenade Sir-William-Osler, Office: Room 469; Lab: Room 473, Montreal, Quebec H3G 0B1
Tel:(514)-398-7287; Lab: (514)-398-2873/1496; Fax:(514)-398-2983; Email: kalle.gehring@mcgill.ca

"Characterizing and Ameliorating Axonal Transport Defects in ARSACS Mice"- Dr. Thomas Schwartz

Goal 1:  To select the most robust system in which to characterize transport defects in the sacsin -/- mouse.

Goal 2:  To test on sacsin -/- neurons those compounds identified in our screen that can enhance transport of mitochondria.

Goal 3: To screen directly in a sacsin -/- background for compounds that increase mitochondrial motility.

Goal 4: To determine the target protein(s) of compounds identified as promising in Goals 1-3.

Duration: one year
Grant: $99,637
Contact:

Dr. Thomas L. Schwarz

Dr. Thomas L. Schwarz

Dr. Thomas L. Schwarz, Professor, F.M. Kirby Neurobiology Center Children’s Hospital, Boston and Dept.of Neurobiology
Harvard Medical School CLSB 12-130, 3 Blackfan Street, Boston, MA 02115
Tel:(617)-919-2219 (office) or (617)-919-2264 (lab)

"Establishing Sacsin’s Interacome and Completing the First High-Throughput Drug Screen Using an ARSACS Fibroblast Essay"– Dr. Bernard Brais and Dr. Eric Shoubridge

Aim 1: Moving from HEK293 sacsin’s interactome to neuronal sacsin partners. Aim 1.2. Study the impact of lack of sacsin or mutated sacsin on identified partners.

Aim 2: Perform high-throughput drug screening using our ARSACS fibroblast assay to identify molecules that rescue the cytoskeletal phenotype.  further validation (2.2). Aim 2.2 Validations of candidate drugs. 2.2.1 Drugs that successfully restore the vimentin network in ARSACS 366 cell lines will undertake a second screen. In this second assay we will include other ARSACS cell lines as well as our CRISPR/Cas9 Sacs-/- fibroblasts. We will also assay different drug concentrations to establish dose response curves. 2.2.2 Drugs that successfully pass this second screen will be used to evaluate their effect on mitochondrial network, which was shown to be disrupted in ARSACS cells (Girard et al., (2012) by standard immunofluorescence and mitochondrial respiratory function by oxygraphy.

Duration: one year
Grant: $100,000
Contacts:

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

Dr Eric Shoubridge

Dr Eric Shoubridge

Dr. Eric Shoubridge, Montreal Neurological Institute and Hospital
3801 University Street Montreal, Quebec, Canada H3A 2B4
Tel: (514)-398-1997; Email: eric.shoubridge@mcgill.ca

"Identification of cellular mechanisms underlying TPS-100 rescue of motor function in ARSACS mice" – Dr. Alanna Watt and Dr. Anne McKinney.

The McKinney and Watt labs, which are located in close proximity in the Bellini Life Sciences Complex and who already share a mouse colony of ARSACS mice (Sacs-/-) will determine the physiological mode of action of TPS-100 a pharma and aminopyridines on Purkinje cell function, including synaptic input and output. They will work closely together, to elucidate the mechanism of action of TPS-100, which has been shown to rescue motor function in ARSACS mice (personal communication,B. Brais), or similar other therapeutic agents. This work will advance the goal of a therapeutic intervention for ARSACS.

Duration: 2nd year of the project
Grant: $140,000 per year
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

Anne McKinney

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

"Investigating the Link Between Impaired Mitochondrial and Calcium Dysregulation in SACS/Purkinje Neurons " – Dr. Francesca Maltecca

The research project has three specific objectives: to test the distribution of mitochondria in distal dendritic branches of Sacs primary PCs; to evaluate dysregulation of Ca2+ homeostasis in Sacs mice and finally to test the efficacy of targeted therapy in Sacs mice.

Duration: 2 years
Grant: $200,000
Contact:

Dr. Francesca Maltecca

Dr. Francesca Maltecca

Dr. Francesca Maltecca, Phd, Neurogenomics Unit(4A2)
San Raffaele Scientific Institute,Via Olgettina,58,20132 Milan, Italy
Tel:39 022643.9116; 022643.4777; Email: francesca.maltecca@hsr.it