Modelling multi-factorial neurodegeneration in Parkinsons disease: removing roadblocks towards the clinic
Parkinson's disease|Neurodegenerative disease in general
Modelling multi-factorial neurodegeneration in Parkinsons 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.