Identification of Network, Activity, and Behavioral Signatures of LRRK2 Expression
LRRK2 Biology Consortium, 2017
Promising Outcomes of Original Grant:
Our original project investigated how the LRRK2 mutation, the principal genetic cause of Parkinson's disease (PD), alters brain activity involved in movement control and sleep quality. In line with our original hypothesis, we observed that pre-clinical models with the LRRK2 mutation slept less and had more powerful sleep spindles, a form of brain wave involved in maintaining sleep and forming memories. These observations suggested that specific connections in the brain associated with the control of sleep are affected by the LRRK2 mutation and that changes in these brain waves could serve as biomarkers (measures of disease activity) in those with PD for early diagnosis and treatment.
Objectives for Supplemental Investigation:
Our follow-up investigation builds upon and extends our previous study in three ways. First, the present study replaces the LRRK2 genetic pre-clinical model used in the previous study with a much-improved "knock-in" (genetic insertion) pre-clinical model that should produce more reliable disease symptoms. Second, the new study tests whether a novel drug, a LRRK2 kinase inhibitor (drug that blocks LRRK2 function), can reverse changes observed in the LRRK2 pre-clinical models, such as the previously identified enhancement of "sleep spindles" -- such a result would suggest that kinase (protein) inhibition is an effective route toward treatment. Finally, motivated by evidence that circadian rhythms (internal body clocks) are disrupted in Parkinson's, the present study now includes 24-hour neural recordings to observe any changes that occur throughout the day that are caused the LRRK2 mutation.
Importance of This Research for the Development of a New PD Therapy:
Parkinson's disease results in profound changes in the connections within and between brain regions. These changes alter sleep quality and sleep-associated brain activity. The present study will investigate the effectiveness of a new drug at reversing the impact of LRRK2 protein expression on the sleep spindle, a type of brain wave involved in sleep maintenance and memory consolidation. If successful, results from this experiment would suggest a novel drug treatment for those with PD who carry LRRK2 mutations. Furthermore, this study may identify surgical targets for deep brain stimulation (surgical technique that delivers electrical pulses to brain cells to decrease symptoms of PD) and new biomarkers of the progression of the disease.
Location: Tucson, Arizona, United States