Study Rationale:
Protein misfolding and aggregation is likely to be a central mechanism in the neurodegenerative changes seen in Parkinson’s disease (PD). The Canadian partner in this project has developed a technique — based on delivery of a small, brain-penetrating peptide — that has the property to induce selective breakdown of alpha-synuclein, the key disease-causing protein in PD. In this project we will evaluate this treatment that holds promise to reduce protein aggregation and protect affected neurons against degeneration.
Hypothesis:
In this experiment we will investigate to what extent this treatment can prevent the aggregation of alpha-synuclein and block neurodegeneration in a pre-clinical model of PD.
Study Design:
The work includes two sets of experiments. First we ask the question whether daily treatment with the peptide, administered systemically, will be effective in reducing the level and aggregation of alpha-synuclein in a model that simulates the alpha-synuclein-induced toxicity seen in PD patients. If the result of this experiment is positive, we will proceed to perform a long-term neuroprotection experiment. In this experiment models overexpressing alpha-synuclein in midbrain dopamine neurons will be treated with daily injections of the active peptide (or an inactive peptide as control) over six weeks, and the magnitude of alpha-synuclein induced pathology and dopamine neuron cell death will be assessed.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
A positive outcome of these experiments will open up an entirely new strategy for disease-modifying treatment in PD patients. The type of peptides explored here are already in use clinically, and, since the ones used here are designed to target alpha-synuclein selectively, they are likely to be well tolerated in humans.
Next Steps for Development:
In case the results in our model are positive we will discuss with MJFF staff how to proceed with further pre-clinical experiments with the goal to develop this approach toward clinical application.