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Behind many a Parkinson’s case lurks a mutation in a gene called LRRK2 — why?

Behind many a Parkinson’s case lurks a mutation in a gene called LRRK2 — why?

Genetic mutations affecting a single gene play an outsized role in Parkinson’s disease. They are generally responsible for the mass die-off of a set of dopamine-secreting (or dopaminergic) nerve cells in the brain involved in, among other things, physical movement. The pathogenic genetic variants of the gene, which goes by the acronym LRRK2 (pronounced “lurk 2”), share a common tendency: They cause the protein LRRK2 encodes to run in constant overdrive, upsetting the delicate balance of a healthy cell.

What ties defective LRRK2 so strongly to Parkinson’s in particular has been a mystery. But a new eLife study by Stanford biochemist Suzanne Pfeffer, PhD, and her colleagues appears to have pulled together several major pieces of the puzzle.

Most cases of Parkinson’s are sporadic, meaning the condition seems to hit individuals at random rather than run in their families, presumably due to an inherited factor. But even in sporadic cases, genetic mutations can figure in.

Of the numerous different LRRK2 variants suspected of predisposing people to Parkinson’s, so far five have been solidly identified as boosting Parkinson’s risk. Taken together, these LRRK2 mutations have been implicated in about 10 percent and 4 percent, respectively, of familial and sporadic cases among Caucasians. Just a single one of those LRRK2 variants is responsible for about 40 percent of familial Parkinson’s cases and 13 percent of sporadic cases among Ashkenazi Jews. 

Drugs targeting LRRK2 are already in clinical trials for Parkinson’s despite the absence of a real understanding of what the corresponding protein is up to.

Pfeffer and her colleagues have previously reported that mutant LRRK2 renders some classes of nerve cells deficient in their ability to create an important subcellular structure called the primary cilium, which acts analogously to a radio reception tower — except that instead of sucking in lengthy waves of incoming electromagnetic radiation, the primary cilium slurps up signaling substances from its surrounding environment.

It’s easy to imagine how a cell lacking such a tower could go astray. But Pfeffer’s team wanted to know why the defect preferentially leads to Parkinson’s disease as opposed to a number of other neurodegenerative disorders.

In the new study, they unraveled a complicated molecular explanation: First, cells lacking primary cilia are unable to respond to a powerful chemical messenger with the anomalously adorable moniker “sonic hedgehog.” Second, the scientists learned, the types of cells that can’t make a decent primary cilium when their LRRK2 protein is in overdrive include a set of cholinergic nerve cells (these secrete acetylcholine, a key nerve-impulse-transmitting substance).

The cholinergic cells in question is known have a close working relationship with the dopaminergic cells implicated in Parkinson’s disease. (Recall that symptoms of Parkinson’s arise when many of the dopaminergic cells die.) When the dopaminergic cells need some help, they pump out sonic hedgehog. Cholinergic cells with functioning primary cilia respond by secreting a molecule that supports dopaminergic cells’ health, and without which  they become death-prone.

So a LRRK2 protein in overdrive leads to no primary cilia which leads to no response to the sonic hedgehog signal which leads to no chemical help for the dopaminergic cells and, therefore, to their death.

Could the breakdown of that support system underlie the unrelenting loss of dopaminergic cells in Parkinson’s? Pfeffer’s lab is now hard at work characterizing, in more detail, this possibly essential back-scratching arrangement and how hyperactive LRRK2 fouls it up.

Photo by Bill Strain

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