October 30, 2017Neurology
A new study published online in the journal Neuron (19 October 2017) provides new evidence on the normal function of LRRK2, the most common genetic cause for late-onset Parkinson's disease. According to the NIH, for more than 10 years, it has been known that mutations in the LRRK2 gene can lead to Parkinson's disease, yet both its role in the disease and its normal function in the brain have remained unclear. In this new study in the mouse, it was demonstrated that LRRK is necessary for the survival of dopamine-containing neurons in the brain, the cells most affected by Parkinson's. Importantly, this finding could alter the design of treatments against the disease.
LRRK2 is found along with a closely related protein, LRRK1, in the brain. A mutation in LRRK2 alone can eventually produce Parkinson's disease symptoms and brain pathology in humans as they age. In mice, however, LRRK2 loss or mutation does not lead to the death of dopamine-producing neurons, possibly because LRRK1 plays a complementary or compensatory role during the relatively short, two-year mouse lifespan.
To better understand the roles of these related proteins in brain function using animal models, the authors created mice lacking both LRRK1 and LRRK2. Results showed that a loss of dopamine-containing neurons in areas of the brain consistent with PD beginning around 15 months of age. When the authors looked at the affected brain cells more closely, they saw the buildup of a protein called a-synuclein, a hallmark of Parkinson's, and defects in pathways that clear cellular garbage. At the same time, more dopamine-containing neurons also began to show signs of apoptosis, the cells' self-destruct mechanism.
While the deletion of both LRRK1 and LRRK2 did not affect overall brain size or cells in such areas of the brain as the cerebral cortex and cerebellum, the mice showed other significant effects such as a decrease in body weight and a lifespan of only 15 to 16 months. Thus, the authors were unable to study other Parkinson's-related effects such as changes in behavior and movement nor were they able to conduct a long-term analysis of how LRRK's absence affects the brain.
Interestingly, the most common disease-linked mutation in LRRK2 is thought to make the protein more active. As a result, most efforts to develop a treatment against that mutation have focused on inhibiting LRRK2 activity. Therefore, according to the authors, the fact that the absence of LRRK leads to the death of dopamine-containing neurons suggests that the use of inhibitory drugs as a treatment for Parkinson's disease might not be the best treatment approach. The authors are now developing mice that have LRRK1 and 2 removed only in the dopamine-containing neurons of the brain. This specific deletion will allow for the ability to study longer-term and behavioral changes while avoiding the other consequences that lead to a shortened lifespan.