Unravelling the interaction between LRRK2 and alpha synuclein
Original article: The unlikely partnership between LRRK2 and alpha-synuclein in Parkinson’s disease, European Journal of Neuroscience : September 30, 2018.
This review outlines the wide range of evidence, from genetic studies in people with Parkinson’s to animal models, which supports multiple potential interactions between alpha synuclein and LRRK2. These potential mechanisms range from events occurring between and inside neurons, including mitochondrial dysfunction, as well as immune cells and astrocytes.
Why is it important?
Although these interactions between alpha synuclein and LRRK2 have not yet been definitively accounted for, researchers are making significant progress in unravelling the precise ways in which they could lead to the different forms of Parkinson’s. Understanding these mechanisms could be important in paving the way toward disease modifying therapies.
Alpha synuclein is a protein which is found normally in neurons, particularly where they make connections with other neurons, as well as at mitochondria, which are the major power plants of the cell. When it changes shape and misfolds, alpha synuclein causes significant damage to neurons. It can also move from one neuron to another, spreading dysfunction across populations of neurons. It is encoded, and so made, according to instructions provided by the gene SNCA, and is thought to be a hallmark of Parkinson’s.
LRRK2 is another protein, which has the ability to modify other proteins, and mutations or pathological changes in the LRRK2 gene have been linked to familial Parkinson’s, although these effects appear to vary depending on the population. In Western populations, they are thought to account for 5-6% of familial cases of Parkinson’s, and 1-2% of non-familial, idiopathic Parkinson’s. However, one recent study in Morocco reported up to 70% of late onset cases were LRRK2 mutation carriers. Conversely, these mutations are very low in Asian populations.
Although the specifics of how LRRK2 mutations cause damage to neurons are not yet known, the important question arises: does LRRK2 interact with alpha synuclein and increase the potential for the emergence of Parkinson’s?
The authors review several decades’ worth of research findings in an attempt to answer this question. Studies have shown that LRRK2 mutation carriers don’t present with Parkinson’s at a younger age. However, some studies found that people with a specific SNCA mutation as well as a LRRK2 mutation have an earlier onset of Parkinson’s, by about a decade. This suggests an interaction. Indeed, further studies in gene knock out mouse models of Parkinson’s found that when the LRRK2 gene was inhibited, the damage caused by alpha synuclein to neurons was dramatically lower. This indicates that there is a basic interaction between LRRK2 and alpha synuclein in Parkinson’s, outside of genetic mutations.
There are many potential ways in which this interaction may occur, for example, within the neuron, where LRRK2 may directly modify alpha synuclein. LRRK2 may also directly affect interactions between neurons, by increasing their propensity to release alpha synuclein, and increasing its transmission potential. Another possible mechanism focuses on interactions between neurons and the immune system. LRRK2 is also found in different types of immune cells. Once more, animal studies provide a rich source of evidence suggestive of yet another intriguing possibility: alpha synuclein has the ability to trigger an immune response, leading to potentially damaging neuroinflammation around the body, an effect which is increased by mutant LRRK2. In addition, neuroinflammation can engage non-neuronal glial cells in the brain, such as astrocytes. Indeed, a recent study (also summarized on PM) showed that the beneficial effects of GLP1 agonists (such as exenatide) on neurons are in fact mediated by astrocytes.
Finally, the authors focus on dysfunction in mitochondria. Interactions between LRRK2 and alpha synuclein appear to be linked to two potential mechanisms in relation to mitochondria: the first mechanism focuses on disrupting energy production and the second on the dynamics that govern their overall shape and function. Another line of research has focused on autophagy, which is the appropriate break down of dysfunctional mitochondria. LRRK2 and alpha synuclein have been shown to cause problems in this important process, which may account for harmful downstream effects.
Research is ongoing in pursuit of each of these potential mechanisms, which ultimately may play out subtly different in people with Parkinson’s. Ultimately, this work has the real potential to bring us closer to cures.
Original article: The unlikely partnership between LRRK2 and alpha-synuclein in Parkinson’s disease, European Journal of Neuroscience : September 30, 2018. Cresto, N., Gardier, C., Gubinelli, F., Gaillard, M. C., Liot, G., West, A. B., & Brouillet, E.