Alpha-synuclein is a tiny protein found in the neurons of your brain. One of its important jobs is to stabilize tiny bags of dopamine so that they may be released at the synapse where one nerve communicates with another. This makes it a very important little protein.
The problem is that alpha-synuclein, like any protein, has a three-dimensional shape and must be folded correctly. If it is not, bad things happen. One of the bad things that we have learned in recent years is that “misfolded” alpha-synuclein appears to be able to spread by causing other normal alpha-synuclein to also misfold. I think of it like one bad apple spoiling whole bunch. Once misfolded alpha-synuclein accumulates it cannot be used and cannot be broken down and forms Lewy bodies. Lewy bodies, clumps of proteins in the affected neurons, are the pathologic hallmark of PD.
Diagnosis
The good news is that in recent years studies have shown that alpha-synuclein may be used to diagnose Parkinson’s disease. These misfolded proteins have been detected on biopsies of the GI tract and in the salivary glands. It appears that the FDA may soon approve a test to diagnose PD by needle biopsy of the salivary gland. Studies of early and advanced Parkinson’s patients have shown positivity in about 75% of patients (1).
Therapy
Alpha-synuclein is also a target for therapy. After multiple animal trials, there have been three human studies involving monoclonal proteins targeting alpha-synuclein. These monoclonal proteins are antibodies which target alpha-synuclein. Antibodies are little Y-shaped proteins that our immune system produces to fight virus, bacteria, and any foreign protein. The idea with this drug was to target alpha-synuclein as a foreign protein. The first trial was with healthy subjects and was able to completely bind all alpha-synuclein found in the blood. The drug was very well tolerated. To learn more about this visit www.clinicaltrials.gov and type in the search bar NCT02095171. An ongoing trial with six PD patients in multiple centers around the country will measure alpha-synuclein and the antibodies in cerebrospinal fluid (NCT02157714). A third study with a different monoclonal protein produced by Biogen is being tested and 40 healthy volunteers in Texas and Indiana. There are also vaccines under trial. It should be noted that animal studies have shown removal of Lewy bodies and resolution of abnormal behaviors in animal models of PD, making vaccine a very attractive possibility (2). AFFiRis has done the only human trial with vaccine in Vienna, Austria. The first phase I study with a vaccine called PD01A was given to 32 early PD patients and, as this was a safety study, was tolerated quite well (3). Patients were entered into long-term follow-up and the data is not back on that yet.
Other Drugs
There was a press release a few months back about the drug Nilotinib reporting marked improvements in a few PD and LBD patients. Nilotinib is already FDA approved for the treatment of chronic myelogenous leukemia, and was shown in a mouse model to reduce the activity of an enzyme called c-Abl (4). c-Abl is activated in PD patients and is associated with overproduction of alpha-synuclein. Animal studies have shown that injection of either alpha-synuclein or c-Abl will increase levels of the other; excess of either can lead to LB formation and cell death. Nilotinib is currently in a phase I clinical trial for the treatment of PD and DLB (NCT02281474) at Georgetown U. The study will measure changes in alpha-synuclein and the protein tau as the primary outcomes, and will include 36 iPD patients.
A phase III study of 86 patients with a form of parkinsonism called MSA at University of Munich is currently recruiting participants (NCT02008721) for the compound EGCG, a polyphenol found in green tea and widely used in dietary supplements. It has been shown to inhibit the formation of toxic alpha-synuclein (5). There is no data as yet.
There are other trials targeting alpha-synuclein, which should give patients hope. I think we are standing in the doorway to a new era of treatment.
-Bill Stamey, M.D.
1. Movement disorders. 2016:31 (2) 250-56
2. Neuron 2005;46:857-68
3. Park Relat Disord 2012;18(Suppl 1): S11-13)
4. Sci Rep 2014;4:4874
5. Proc Natl Acad Sci USA 2010;107:7710-7715
