Recherche 2016

Aim 1- Mapping GI network of ARSACS-associated SACS target using CRISPR
1.1. Quantitative readout for scoring GIs
1.2. GI validation and benchmarking

Aim 2 – Characterizing ARSACS-linked SACS pathways for function discovery

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

Dr. Mohan Babu

Dr. Mohan Babu

Dr.Mohan Babu, Asst. Professor CIHR New Investigator,Department of Biochemistry University of Regina
Saskatchewan SK S4S 0A2
Tel:(306)-585-4192; Email: mohan.babu@uregina.ca

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: two years
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

Objective 1. To generate in vitro disease model by creating ARSACS disease- specific cerebellar cells via iPSC from patients and healthy individuals as controls which will serve as a tool to depict disease-specific molecular markers.

Objective 2. The comparative functional analysis between control and patient derived cerebellar cells (Purkinje and granule cells) will include molecular, cellular studies focused on detection of cerebellar specific markers through the differentiation and cerebellar electrophysiological recordings

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

Dr.Slaven Erceg

Dr.Slaven Erceg

Dr.Slaven Erceg, Head of Stem Cell Therapies in Neurodegenerative Diseases
Research C enter « Principe Felipe », Valencia (Spain)
Email: serceg@cipf.es

The objective is to identify compounds that will improve axonal transport in neurons carrying the mutation. The compounds we will survey are ones with a known mechanism of action and thus will identify cellular signaling pathways with the potential to overcome the transport deficits. These pathways are likely to include drug‐able targets that could ultimately serve as a point of therapeutic intervention. Strategy: Cultured neurons from the sacsin knockout mouse will be employed in this project. Identifying compounds that improve mitochondrial transport in these cells will have four component aims. The first will be to examine transport in detail in multiple neuronal cell types and developmental stages in order to find a suitable system for characterization and screening. The second stage will involve a detailed characterization of the transport defect to determine if it is indeed mitochondrion‐specific or influences multiple cargoes and whether it alters both anterograde and retrograde movement. The third stage will take advantage of a medium‐throughput compound screen currently being performed in my laboratory to identify compounds that alter mitochondrial transport in wildtype hippocampal neurons. « Hits » identified in this screen that increase transport will be tested on the sacsin mutant neurons to see if they can restore normal transport. In the fourth stage a medium‐throughput screen for compounds of known mode of action will be conducted using the sacsin mutant neurons. The power of this latter approach lies in its choice of endpoint. By using mitochondrial motility as an endpoint, compounds of value can be recognized regardless of whether they act directly and solely on mitochondria, or act via amelioration of a change in the cytoskeleton

Duration: one year
Grant: $96,568
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)

The research project is to examine the ARSACS mutations in the J-HEPN fragment of sacsin, to engineer Hsc70 to potentially identify sacsin-directed substratesand to address whether sacsin promotes degradation of neurofilament heavy subunit (NFH)

Duration: one year
Grant: $40,431
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

The greatest bottleneck in structural studies of Sacsin is the preparation and screening of fragments of thousands of Sacsin constructs with different boundaries, different mutations, and sequences from different species. To overcome this, we have developed a high-throughput strategy that relies on chemical DNA synthesis to prepare medium-sized libraries (mixtures) of Sacsin protein fragments. These are analyzed by gel filtration to isolate well-behaved proteins with solubility and stability characteristics that are favourable for structural studies. The proteins with these properties are then identified by mass spectrometry and studied by structural biology. The goal of the high–throughput strategy is to identify well-behaved Sacsin protein fragments for structural studies.

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

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: two years
Grant: $100,000 per year
Contacts:

Dr Peter Mc Pherson

Dr Peter Mc Pherson

Dr. Peter McPherson, Associate 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

The overall objective of the project is to devel+op TPS-100 as a first treatment of ARSACS and to identify a second generation drug based on efficacy and knowledge of receptor pharmacology of TPS-100. Our goal is to synthesize a directed library of compounds with varying Kv channel pharmacology with the goal of enhancing activity at Kv1.2, 1.3, 1.4 relative to Kv1.5 and Kv1.1 which are believed to be associated with potential side effects (Table 2).

Duration: one year
Grant: $100,000
Contact:
Shawn Maddaford, Talon Pharmaceutical Services Inc.
2660 Speakman Drive, Rm A-61 Mississauga, ON L5K 2L1
Tel:(416) 479-0738 ext 102

Continue the investigation of sacsin partners using the BioID assay, using the full length sacsin as well as different sacsin mutants and to further characterize ARSACS fibroblast cytoskeletal disorganization as a cell-based model.

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

The research project has two specific aims: to continue experiments to determine if loss of sacsin functions in NF metabolism plays a central role in pathogenesis of ARSACS and to determine the effect of sacsin domains on the phenotype in our ARSACS culture models and based on those data to develop a therapeutic peptide to move forward in preclinical testing.

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