Recherche 2018

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)

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

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

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.

 

Dr. Paul Chapple

Dr. Paul Chapple

 

 

Duration:  Second year of a three year project
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