Leucine-rich repeat kinase 2 (LRRK2)

Published on December 31, 2023   26 min

Other Talks in the Series: Parkinson's Disease

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Today, I'm going to talk to you about Leucine-rich repeat kinase 2 or LRRK2. My name is Mark Cookson. I'm the Chief of the Laboratory of Neurogenetics at the National Institute on Aging.
First, let me tell you a little bit about Parkinson's disease, what it is, and how it expresses itself in humans. Parkinson's disease is a motor disorder. It's characterized by tremors, bradykinesia, or slowness of movement, rigidity, posture, and gait. However, Parkinson's disease is also a multisystem disorder, so you can have prodromal symptoms that occur before the onset of motor Parkinson's disease including things like REM sleep behavioral disorder. Often, later on in the disease course, Parkinson's disease can develop into a dementing illness characterized by cortical dysfunction. The pathology of Parkinson's disease is really two parts. First of all, the cell loss, and very prominently dopamine neurons in the substantial nigra pars compacta that project to the striatum are lost. But the pathology is also protein accumulation pathology and we have Lewy bodies that are present across different brain regions.
Illustrated here by the work of Heiko Braak et al., you can see that the Lewy body pathology starts in very deep brain stem areas and then progresses up through the midbrain and then eventually, into the cerebral cortex.
Parkinson's disease pathology is also a multicellular process. For example, I said earlier that neurons and substantia nigra the dopamine neurons that project the striatum are lost in the disease. But this is also associated with the activation of cells around those dying neurons, including astrocytes and microglia. If we think of Parkinson's in this way, it's a multi-system, multi-pathology, and multicellular disorder.