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Jean-Pierre Julien,
Ph.D.

Professor, Department of Psychiatry and Neuroscience, Université Laval
Canada Research Chair in neurodegeneration
Director of Axis integrative neuroscience and experimental therapies


Promising discoveries on Amyotrophic Lateral Sclerosis and other neurodegenerative diseases

Amyotrophic lateral sclerosis, also known as ALS or Lou Gherig's disease, is a serious progressive disease that causes the death of motor neurons, which control muscle movement.

The death of motor neurons causes paralysis, which makes walking, speech, swallowing and eventually, breathing impossible. This is a terminal illness, without remission or cure.

Jean-Pierre Julien is a pioneer in ALS research

Professor Jean-Pierre Julien was the first to show that disruption of neurofilaments can cause neurological diseases and to develop immunotherapies to treat ALS. He has developed transgenic mice carrying mutations similar to those seen in humans with ALS, which are important research models. These models allow

  • to better understand the development of the disease and its progression
  • to find intervention targets to inhibit this progression
  • to test new avenues of treatment.

Discoveries leading to new avenues of treatment

Recent research has shown that ALS is associated with the formation of aggregates of a protein called TDP-43. Dr. Julien discovered that this protein associates with a protein regulating inflammation, called NF-kappaB. He then showed that anti-inflammatory drugs could slow the progression of the disease in ALS model mice.

This discovery led to the identification of compounds derived from a plant, Withania somnifera, used in traditional Indian medicine for over 4000 years, which are currently in clinical trials.

Personalized medicine, a reason for hope

The recent identification of dozens of mutated genes in people with ALS partly explains the diversity of forms of ALS, and the divergence in response to various treatments tested.

This discovery now allows researchers to develop therapeutic approaches based on the genetic, environmental and clinical diagnotic characteristics of each patient.

Julien and his team are currently working on identifying and testing small molecules and antibodies that can specifically target the proteins involved in ALS.

The multiplication of therapeutic approaches, made possible by research, offers real hope for patients suffering from ALS, but also other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, which are also accompanied by abnormal accumulations of proteins, including TDP-43.


Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite genetic heterogeneity of ALS, a common hallmark is the presence of TDP-43 protein accumulations in degenerating neurons. My laboratory has generated transgenic mouse lines that develop pathological features of ALS including TDP-43 aggregation. Using these transgenic mice, the first aim of my research program will be to elucidate mechanisms that contribute to the onset and spreading of TDP-43 “proteinopathy”. Based on our discoveries that TDP-43 is a binding partner of the p65 subunit of NF-κB and that inflammation can induce TDP-43 accumulations, we propose to clarify the role of NF-κB pathway. An important effort is also devoted to investigate the prion-like propagated protein aggregation in TDP-43 proteinopathy. The role of exosomes in the intercellular transfer of pathogenic TDP-43 is also being examined. The second aim of my research is to develop innovative treatment for ALS based on our discovery of new therapeutic targets. Our focus in the near future will be on small molecules and single chain antibodies (nanobodies) to target TDP-43 protein interactions and NF-κB activity. In collaboration with a company, we have already developed novel semi-synthetic withanolides which are potent NF-κB inhibitors. Preclinical studies with two lead compounds are now in progress with the plan to move one compound to Phase I clinical trial.


Labo Jean-Pierre Julien

Ph.D. Students:
Vincent Picher-Martel
Sunny Kumar
Banshi Nath

Postdocs:
Kallol Dutta
Silvia Pozzi
Prakash Mishra
Pooja Shree Mishra
Senthil Krishnasamy

Research Assistants:
Daniel Phaneuf
Karine Plourde
Pierre Cordeau
Genevieve Soucy
Christine Bareil


Iguchi Y, Eid L, Parent M, Soucy G, Bareil C, Riku Y, Kawai K, Takagi S, Yoshida M, Katsuno M, Sobue G and Julien JP (2016) Exosome secretion is a key pathway for clearance of pathological TDP-43. Brain in press.

Picher-Martel V, Dutta K, Phaneuf D, Sobue G and Julien JP (2015) Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells. Molecular Brain. On line.

Correia AS, Patel P, Dutta K and Julien JP (2015) Inflammation induces TDP-43 mislocalization and aggregation. PlosOne, on line.

Ohta Y, Tremblay C, Schneider JA, Bennett DA, Calon F, Julien JP. (2014) Interaction of transactive response DNA binding protein 43 with nuclear factor kappaB in mild cognitive impairment with episodic memory deficits. Acta Neuropathol Commun. Apr 1;2(1):37. doi: 10.1186/2051-5960-2-37.

Patel P, Julien JP and Kriz J (2014) Early stage treatment with Withaferin A reduces misfolded superoxide dismutase 1 and extends the lifespan in mouse model of ALS. Neurotherapeutics, 12(1):217-33.

Patel P, Kriz J, Gravel M, Soucy G, Bareil C, Gravel C, Julien JP (2014) Adeno-associated Virus-mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis. Mol Therapy 22 498-510.

Swarup V, Audet JN, Phaneuf D, Kriz J and Julien JP (2012) Impaired sciatic nerve regeneration following axotomy in TDP-43 transgenic mouse models of ALS. J Neurosci. 32:18186-18195.

Millecamps S and Julien JP (2013) Axonal transport deficits and neurodegenerative diseases. Nat Reviews Neurosci. 4, 161-176.

Swarup V, Phaneuf D, Bareil C, Robertson J, Kriz J and Julien J.-P. (2011) Pathological hallmarks of ALS/FTLD in transgenic mice produced with genomic fragments encoding wild-type or mutant forms of human TDP-43. Brain 134: 2610-2626.

Swarup V., Phaneuf D., Dupré N., Petri S., Strong M., Kriz J. and Julien J.-P. (2011) Deregulation of TDP-43 in ALS triggers nuclear factor-κB-mediated pathogenic pathways. J Exp Med, 208(12):2429-2447.


Dr. Julien is recognized as one of the most influential scientists in the field of amyotrophic lateral sclerosis (ALS) and neurodegenerative disease. Dr. Julien obtained his Ph.D. in Biochemistry from McGill University and completed postdoctoral work at the National Institute for Medical Research in London (UK). From 1989 to 2003, he was Professor at the Centre for Research in Neuroscience of McGill University. Since 2003 he holds a Canada Research Chair in Neurodegeneration at Laval University. He has published over 200 peer-reviewed papers, many in top ranked journals such as: Cell, Neuron, Science, Nature, J Exp Med among others. He was awarded the prestigious Sheila Essey Award for research on ALS from the American Academy of Neurology, the prix Léo-Pariseau and the Jonas Salk Award of March of Dimes. He is member of the Canadian Academy of Health Sciences and of the Royal Society of Canada. He is a member of the Robert Packard Center for ALS Research at Johns Hopkins University. He has been a member of advisory board of CIHR Institute of Genetics and on the Gairdner medical review panel. He has been the organizer since 2005 of the Annual Symposium on ALS of the Fondation André-Delambre. He has made important contributions to the current understanding of ALS pathogenesis caused by TDP-43 proteinopathy and mutations in superoxide dismutase (SOD1). He was the first to report that disorganization of neurofilaments can cause motor neuron degeneration in transgenic mice and to develop immunization approaches for ALS treatment. He discovered a new therapeutic target for ALS which involves a key protein of the innate immune response. These findings might form the basis for the development of new experimental therapeutics for ALS and related disorders.


2000 Sheila Essey Award for research on ALS from the American Academy of Neurology.
2003 Personnalité de La Presse. Semaine du 13 avril 2003.
2003 Canada Research Chair in neurodegeneration (Tier 1)
2010 Canada Research Chair in neurodegeneration (Tier 1)
2009 Fellow of the Canadian Academy of Health Sciences
2012 Médaille du Jubilée de la reine Elizabeth II
2013 Prix Léo-Pariseau de l’ACFAS
2013 Lauréat scientifique de l’année 2013 Le Soleil/Radio-canada
2014 Jonas Salk Award from March of Dimes Canada
2016 Fellow of the Royal Society of Canada


Keywords: 
amyotrophic lateral sclerosis, fronto-temporal dementia, immunotherapy, single chain antibody, neurofilament, transgenic mice, withferin, neuroinflammation


 
 
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