http://www.jneuroinflammation.com/co...-2094-9-94.pdf

Parkinson's disease and immune system: is the culprit LRRKing in the periphery?

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain kinase/GTPase that has been recently linked to three pathological conditions: Parkinson's disease; Crohn's disease; and leprosy. Although LRRK2 physiological function is poorly understood, a potential role in inflammatory response is suggested by its high expression in immune cells and tissues, its up-regulation by interferon gamma, and its function as negative regulator of the immune response transcription factor NFAT1. In this review we discuss the most recent findings regarding how LRRK2 could be a player in the inflammatory response and we propose a scenario where the detrimental effects mediated by Parkinson's disease LRRK2 mutations may initiate in the periphery and extend to the central nervous system as a consequence of increased levels of pro-inflammatory factors permeable to the blood brain barrier.

The complete article is available as a provisional PDF.

Madelyn, thanks very much for this reference.

It is beginning to look like the main activity of the normal LRRK2 protein is in the periphery of the body rather than in the brain, and is present at highest levels in circulating immune cells, and has been found to regulate the production of inflammatory cytokines by those cells.

However, the PD-related mutant LRRK2 molecules appear to have lost this regulatory function. As a result, these cytokines are chronically over produced and released into the blood. Because the cytokines, especially the one called TNF alpha can easily pass through the blood brain barrier, they apparently activate microglial cells which surround the dopaminergic neurons of the substantia nigra.

These researchers think that the resulting chronic glial cell inflammatory process damages and eventually wipes out those particular neurons.

There are lots of additional details of this new hypothesis in the paper.

Robert

That really makes sense [the thread]. But isn't LRRK 2 mutation rare and mostly hereditary?


paula