Scientists identify a role for main Parkinson’s gene in the brain.

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

Previous studies show that 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 utilises mice lacking both LRRK1 and LRRK2 to observe a loss of dopamine-containing neurons in areas of the brain consistent with PD beginning around 15 months of age.  Results show a buildup of a protein called α-synuclein, a hallmark of Parkinson’s, in the affected dopamine brain cells and defects in pathways that clear cellular garbage, and cell apoptosis.  Data findings show that inactivation of LRRK2 and its functional homolog LRRK1 results in earlier mortality and age-dependent, selective neurodegeneration.

Results show that LRRK is critical for the survival of the populations of neurons affected by Parkinson’s disease.  Data findings show that 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 surmise their study reveals an essential role of LRRK in the survival of dopamine neurons and in the regulation of the autophagy-lysosomal pathway, which digests intra-cellular cytosolic components, in the aging brain.  For the future, the researchers state that they are now developing mice which have LRRK1 and 2 removed only in the dopamine-containing neurons of the brain.  They conclude that this specific deletion will allow them to study longer-term and behavioural changes while avoiding the other consequences which lead to a shortened lifespan.

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


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