Reaserchers at The Scripps Research Institute (TSRI) reported on a study which focuses on an important enzyme called Parkin whose absence is a cause for an early-onset form of PD
PD is usually a sporadic (non-genetic) condition, and factors which lead to development of the disease include advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins.
Between 5 – 15 percent of PD cases arise specifically from inherited gene mutations.
The Parkin Gene mutation
The most common of these is mutations to the parkin gene.
Patients who have no functional parkin gene typically develop Parkinson’s-like symptoms before age 40.
But how Parkin gene mutations actually lead to the development of the disease was not clear, even though its role as a “ubiquitin ligase” was known for some time.
The next section is a bit technical – so you can skip it to the Conclusion part if the gory details don’t interest you!
The Substantia Nigra in Parkinson Disease – where it all starts!
Basic Science – for those with a stomach for it!
These enzymes typically alter the level of other enzymes. Then it was discovered that the Parkin gene-related ligase enzyme had a role in lowering the levels of a specific protein called Fbw7.
In various experiments involving mice and men, it was realized that loss of the Parkin gene led to rise in the levels of Fbw7.
Other experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder to reduce levels of Fbw7β. Without this reduction in Fbw7β levels, the neurons become more sensitive to “oxidative stress” – so that more of them undergo a programmed self-destruction called apoptosis.
In experiments carried out by other researchers, who were studying the role of Fbw7 β’s role in cancer, it was found that this protein reduced the levels of another protein called Mcl -1, which was responsible for helping cells survive, making them more resistant to apoptosis.
How an enzyme works
So the chain of events is as following: in a patient with a parkin gene mutation, the levels of the specific ligase which it encodes becomes low; this leads to a rise in levels of Fbw7β, which in turn then causes a fall in levels of Mcl -1, which then makes the neurons vulnerable to oxidative stress.
The hypothesis is that in these patients, levels of Fbw7β, which have been proven to be high in the substantia nigra of patients with the Parkin Gene mutation, could be reduced by some means to increase protection against the development of PD.
So what is new?
The mechanism by which Parkin Gene mutations lead to degeneration of neurons specific to PD is gradually being unraveled.
Scientists in the field believe that these mechanism probably also play some role in the garden variety of PD – the sporadic form.
The exciting new thing is that now we have a target – to increase the level of the enzyme encoded by Parkin gene or reduce the levels of another protein which the Parkin Gene-encoded enzyme normally reduces.
The challenge would of course be to identify an easy way to do this, as well as identifying patients early enough in their disease course to make this treatment viable. Usually, by the time PD patients first develop symptoms, 60% of the neurons are already lost.