Study Rationale:
One of the hallmarks of Parkinson's disease (PD) is the presence and aggregation (clumping) of a misfolded protein called alpha-synuclein; however, we do not know how this misfolding happens. In 2003, Braak and colleagues suggested that alpha-synuclein pathology was "transmissible" (contagious). Additionally, studies have shown that normal dopamine neurons transplanted into Parkinson's cells quickly acquired this misfolded alpha-synuclein pathology. The goal of this project is to directly test if aggregated alpha-synuclein, made of preformed fibrils (PFF), can recruit the normal protein to its abnormally aggregated form and then examine if this activates the immune system in the brain. We will also examine if this effect depends on the part of the brain where the misfolded alpha-synuclein exists.
Hypothesis:
We hypothesize that misfolded alpha-synuclein in the form of PFFs will induce normal alpha-synuclein to misfold and initiate an abnormal immune response in the brain which will lead to other parkinsonian pathologies in the basal ganglia (brain region affected by PD) but not in parts of the brain that are unaffected in Parkinson's.
Study Design:
Misfolded alpha-synuclein in the form of PFFs will be injected into two parts of the brain: the striatum, which is affected in PD, and the hippocampus, which is not affected in PD. Using a variety of neuroanatomical and biochemical measures, we will examine if the PFFs induce normal alpha-synuclein to misfold, as well as determine if the injected PFFs induce an abnormal immune response.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Currently, the main goal of PD treatment is to reduce its symptoms. The goal of this study is to identify a new mechanism in which PD can progress. If we find that abnormal misfolded protein can change normal protein into a pathological state and induce progressive parkinsonism, we may identify a new target for PD.
Next Steps for Development:
If we find that misfolded alpha-synuclein can induce normal alpha-synuclein to alter its structure, we can use this information to develop new drugs or biologics to interfere with this process and potentially slow or stop the progression of Parkinson's disease.