Establishing a new link between brain and body
USP19 as a novel therapeutic target for impeding cell-to-cell propagation of a-synuclein in Parkinson’s disease
A disease of the brain can become a disease of the entire body, as the breakdown of neural pathways often leads to a loss of muscle mass. Simon Wing, a professor in McGill University’s Department of Endocrinology and Metabolism, is eager to examine this potential connection as it applies to Parkinson’s disease. He has only recently discovered the possibility of such a link, but it could offer a new perspective on some of the most fundamental aspects of this condition.
“Through my research over the last 15 years I found a gene that encodes an enzyme that appears to be important in muscle wasting,” he explains. “This gene is called USP19.”
Wing was already studying the behaviour of this gene when he was contacted by a U.S. researcher who discovered that USP19 may also be tied closely to a problematic aspect of Parkinson’s disease. At the heart of this problem is a protein called α-synuclein, which forms clumps of disruptive material within brain cells. Not only does this material interfere with the ability of these cells to produce dopamine, these affected cells also appear to transmit α-synuclein to other brain cells, so that the disease spreads and causes more disability.
“Our work is based on a model where Parkinson’s disease spreads because α-synuclein is transferred from a sick neuron to a healthy neuron,” says Wing. “However, nobody really knows how α-synuclein gets out of the neuron.”
That detail is crucial, because if researchers can identify and block the transmission mechanism, it might be possible to design a treatment to stop α-synuclein from leaving affected cells—stopping Parkinson’s in its tracks. Wing’s U.S. colleague was therefore interested in USP19, which appears to serve as a mediator of this process. More importantly, Wing’s laboratory was already home to mice that have been genetically altered to remove USP19.
“If we look at our mice that do not have USP19 and so presumably cannot use this pathway to push α-synuclein out of the neuron, are they protected against the progression of Parkinson’s disease?” asks Wing. If so, then this finding would pinpoint this gene as a valuable target for possible therapies.
Wing admits that this prospect remains an open question, but one worth exploring because of its novelty and exciting possibilities. He also acknowledges that this foray into Parkinson’s disease has been a learning experience for him, one that has led him to work with some of the top people in the field at the Montreal Neurological Institute.
“It could be quite transformative,” he concludes. “There are groups already working on developing drugs to block USP19. We could be able to move fairly quickly over a few years into clinical trials if our hypothesis is correct.”