Thursday , June 8 2023

The puzzle of a mutant gene hidden behind many Parkinson's cases


Immunohistochemistry for the alpha-synuclein showing positive staining (brown) of an endogenous Lewy-body to substance Substantia nigra in Parkinson's disease. Credit: Wikipedia

Genetic mutations affecting a single gene play a huge role in Parkinson's disease. Mutations are generally responsible for the massive rejection of a set of dopaminergic or dopaminergic nerve cells in the brain involved in physical movement.

Pathogenic variants of the gene, LRRK2, share a common trend: they cause the coding protein to run into continuous excessive vibration, reversing the delicate balance of a healthy cell.

What links LRRK2 so mildly with Parkinson's disease has troubled the researchers. Now, a study led by the medical school scientists seems to have compiled a large part of this puzzle.

Suzanne Pfeffer, Ph.D., Professor of Biochemistry and Professor Emma Pfeiffer Merner in Medical Science, is the senior author of the study, published on November 6 eLife. The main authors are the postdoctoral dissertations Herschel Dhekne, Ph.D., and Izumi Yanatori, Ph.D.

Random Parkinson's disease

Most cases of Parkinson's are sporadic, which means that the situation seems to be hitting people in random rather than running in their families. But even in sporadic cases, genetic mutations can be found.

Of the many LRRK2 variants suspected of predisposing people to Parkinson's, so far five have been identified as strong risks for Parkinson's. Overall, these LRRK2 mutations have been implicated in about 10% of inherited cases and in 4% of sporadic cases between the caucuses. Only one of these mutations is responsible for about 40% of Parkinson's family cases and 13% of sporadic cases between the Ashkenazi Jews.

Drugs targeting LRRK2 are already in clinical trials for Parkinson despite the lack of a real understanding of their role in the disease.

Pfeffer and colleagues have previously reported that the mutant LRRK2 renders certain classes of nerve cells inadequate in their ability to create a significant subcellular structure called the main cell which acts according to a radio receiving tower, to absorb electromagnetic radiation waves, the core kills signaling substances from the environment.

It is easy to imagine how a cell lacking such a receiving tower could be deformed. But the Pfeffer team wanted to know why the defect leads to Parkinson's disease, as opposed to a series of other neurodegenerative disorders.

A complex molecular explanation

In the new study, the researchers surpassed a complex molecular explanation: First, cells lacking a primary eyelash are unable to respond to a powerful chemical messenger known as a sonic hedgehog. Second, scientists have learned that cell types that can not make a decent primary cavity when the LRRK2 protein is overdose include a series of cholinergic nerve cells so named because they secrete acetylcholine rather than dopamine or other nerve cell-signaling substances.

These cholinergic cells have a close working relationship with dopaminergic cells involved in Parkinson's disease. When dopaminergic cells need some help, they pump the sonic hedgehog. Cholinergic cells with functional primary layers respond to the secretion of a molecule that keeps the dopaminergic cells healthy. Without this molecule, dopaminergic cells become more vulnerable to death.

Thus, an LRRK2 protein in overdrive does not lead to primary cilia, which leads to no response to the hedgehog sound signal, which does not lead to chemical help for dopaminergic cells and hence to their death.

Can the disruption of this support system be the basis for the relentless loss of dopaminergic cells in Parkinson? Pfeffer's lab is now hard at work, studying this very question.

Explore further:
The Parkinson's treatments that are being developed could benefit most people with the disease

More information:
Herschel S Dhekne et al. A pathway for Parkinson's LRRK2 kinase to inhibit primary eyelashes and signal the hedgehog to the brain, eLife (2018). DOI: 10.7554 / eLife.40202


Provided by:
Stanford University Medical Center

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