Blanc SVSE 4 - Blanc - SVSE 4 - Neurosciences

Modelling multi-factorial neurodegeneration in Parkinson’s disease: removing roadblocks towards the clinic – TARGET PD

Modelling multi-factorial neurodegeneration in Parkinson’s disease:

To date, NO mammalian model recapitulates the required age-dependent parkinsonian degeneration, the a-synuclein-inclusion pathology, the PD pathophysiology as well as the broad range of motor and non-motor parkinsonian symptoms. This absence prevents the development of neuroprotective and neurorestorative therapeutic strategies, constituting a fatal roadblock for both academia and industry in translating research into clinically-relevant discoveries.

Modelling for derisking the translation

Epidemiological and clinical evidences strongly suggest that PD results from a multifactorial etiology involving both genetic susceptibility factors and environmental exposures superimposing upon aging, the major risk factor for PD. Such multifactorial nature of the degenerative causes and processes has been overlooked so far, explaining the failure in truly replicating PD in mammals.

We here propose four categories of mechanisms that we will combine into an integrated framework: (i) the role of aging, (ii) the role of the lysosomal dysfunction(s), (iii) the role of a-synuclein acting in a potential prion-like manner and, of paramount importance, (iv) the greater susceptibility of primate dopamine neurons versus rodent dopamine neurons for PD degeneration.

The series of innovative proprietary PD models of ascending complexity will culminate with the creation of genetically-engineered primates. That TARGET PD will fertilize frontier research with pioneer ideas that will increase France competitiveness while paving the way toward rock solid preclinical validation of neuroprotective treatments for PD and beyond, justifies accepting the challenge.

Target PD is organized in parallel research projects that will reach a succession of specific milestones, which in themselves constitute frontier research objectives. Achieving these intermediate keystones will allow the progressive transfer of increasingly-complex, multi-dimensional, hopefully heuristic, models that will be able to improve the translational value of preclinical development of therapeutic strategies, not mentioning the gain in knowledge of intrinsic cell death mechanisms.

(C) Illustrative images (top) and quantification (bottom) of TH-positive striatal terminals by optical densitometry or of TH-positive SNpc neurons by stereology, in non-injected and LB-injected monkeys. *p<0.05 compared with non-injected animals. (D) Repr

Despite unprecedented progress in the understanding of neurodegenerative mechanisms in Parkinson’s disease (PD), thanks to the discovery of mutations in several genes, NO mammalian model recapitulates the required age-dependent parkinsonian degeneration, the a-synuclein-inclusion pathology, the PD pathophysiology as well as the broad range of motor and non-motor parkinsonian symptoms. This absence prevents the development of neuroprotective and neurorestorative therapeutic strategies, constituting a fatal roadblock for both academia and industry in translating research into clinically-relevant discoveries. Epidemiological and clinical evidences strongly suggest that PD results from a multifactorial etiology involving both genetic susceptibility factors and environmental exposures superimposing upon aging, the major risk factor for PD. Such multifactorial nature of the degenerative causes and processes has been overlooked so far, explaining the failure in truly replicating PD in mammals. We here propose four categories of mechanisms that we will combine into an integrated framework: (i) the role of aging, (ii) the role of the lysosomal dysfunction(s), (iii) the role of a-synuclein acting in a potential prion-like manner and, of paramount importance, (iv) the greater susceptibility of primate dopamine neurons versus rodent dopamine neurons for PD degeneration. TARGET PD will thus innovatively model in mouse and primate species the interaction of these causes of cell death in PD and relate PD-relevant symptoms to degeneration of identified brain nuclei. The series of innovative proprietary PD models of ascending complexity will culminate with the creation of genetically-engineered primates. That TARGET PD will fertilize frontier research with pioneer ideas that will increase France competitiveness while paving the way toward rock solid preclinical validation of neuroprotective treatments for PD and beyond, justifies accepting the challenge.

Project coordinator

Monsieur Erwan BEZARD (Institut des Maladies Neurodégénératives) – erwan.bezard@u-bordeaux2.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IMN Institut des Maladies Neurodégénératives

Help of the ANR 559,874 euros
Beginning and duration of the scientific project: November 2012 - 48 Months

Useful links