Parkinson’s disease (PD) is a long-term neurodegenerative disorder of the central nervous system whose symptoms generally come on slowly over time, mainly affecting the motor system.  The most common genetic cause of PD is a mutation in the LRRK2 loci, however, this gene’s normal physiological role in the brain is unclear.  Now, a study from researchers at the National Institutes of Health shows the LRRK gene is necessary for the survival of dopamine-containing neurons in the brain, the cells most affected by Parkinson’s.  The team states their findings could alter the design of treatments against the disease.  The study published in the journal Neuron.

Previous studies show 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.  The current study investigates the roles of these closely related proteins in brain function using animal models.

The current study utilizes mice lacking both LRRK1 and LRRK2 proteins to observe a loss of dopamine-containing neurons in areas of the brain consistent with PD.  Results show a buildup of a protein called α-synuclein, a hallmark of Parkinson’s, in the affected dopamine brain cells.  Data findings show inactivation of LRRK2 and its functional homolog LRRK1 results in earlier mortality and age-dependent, selective neurodegeneration.

Results show LRRK is critical for the survival of the populations of neurons affected by Parkinson’s disease.  Data findings show 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.

The team surmises their study reveals an essential role of LRRK in the survival of dopamine neurons and in the regulation of the dead cell and debris clearance pathway in the aging brain.  For the future, the researchers state they are now developing mice that have LRRK1 and 2 removed only in the dopamine-containing neurons of the brain. 

Source: National Institute of Neurological Disorders and Stroke (NINDS)

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