In studies with laboratory mice, scientists have identified a single molecule, an enzyme called c-Abl, that regulates the build-up of toxic alpha-synuclein protein in brain cells. Such protein clumps, known as Lewy bodies, are the hallmark of Parkinson’s disease (PD). The finding suggests that blocking the enzyme may be an effective approach for new therapies to treat PD. The research appears in the June 27 online edition of The Journal of Clinical Investigation.
Scientists have long known that the brain cells affected by PD contain clumps of alpha-synuclein protein. These clumps only can be seen on autopsy. Autopsy studies also have shown that the enzyme c-Abl is especially active in the brains of people with PD. Furthermore, in experiments with laboratory mice engineered to have PD, blocking c-Abl and other substances slowed disease progression.
For the new study, researchers led by Han Seok Ko, Ph.D., at The Johns Hopkins University School of Medicine, investigated the effects of blocking c-Abl specifically, and not other molecules. They studied mice genetically engineered to have excess alpha-synuclein and PD-like symptoms, some of which either made no c-Abl at all or produced extra amounts of the enzyme. The scientists also investigated the molecular details of how c-Abl interacts with alpha-synuclein.
- Mice engineered to lack c-Abl had less clumping of alpha-synuclein and less severe PD symptoms.
- Dialing up the amount of c-Abl in mice already prone to PD resulted in more protein clumps in their brains, more severe PD symptoms and faster disease progression.
- Increasing c-Abl in normal mice caused them to develop PD.
- The enzyme c-Abl puts a chemical tag on a specific spot on the alpha-synuclein molecule, which makes those molecules more likely to stick to each other.
What Does It Mean?
The new study shows how an enzyme, c-Abl, plays a role in causing PD, and suggests that therapies that block c-Abl could potentially change the course of the disease. These findings are especially timely because of a recent small open label study of a c-Abl blocker called nilotinib in people with PD and Lewy body disease. The c-Abl enzyme is a key player in a form of leukemia called CML (chronic myeloid leukemia). Therefore, multiple drugs which block it (including nilotinib) have been developed. Most of these drugs imitate antibodies which target this enzyme specifically. Considered chemotherapy, their side effect profile is often more benign than traditional chemotherapy agents yet serious adverse side-effects remain an issue, especially when considered for a chronic disease such as Parkinson's, that many people live with for decades.
Understanding how c-Abl contributes to PD not only serves as a basis for developing new therapies, but also helps speed research on the underlying causes of the disease. In addition, the study authors conclude, the chemical tag that c-Abl places on α-synuclein might be useful as a measure, or biomarker, of disease progression.
Brahmachari S, Ge P, Lee SH et al. (2016). Activation of Tyrosine Kinase c-Abl Contributes to α-Synuclein–Induced Neurodegeneration. J Clinical Investigation http://dx.doi.org/10.1172/JCI85456