NIH Director Blogs on MJFF-Supported Study Linking LRRK2 Mutations to Alpha-Synuclein Clumping

Scientists Find New Marker to Measure LRRK2 ActivityToday, Francis Collins, MD, PhD, the director of the National Institutes of Health, writes about critical “new insight” into a possible cause of Parkinson’s disease (PD). Collins’ blog centers around a report from a team of researchers at the Albert Einstein College of Medicine that used Michael J. Fox Foundation (MJFF) research tools, called antibodies, in order to complete their study.

The report, from study lead Ana Maria Cuervo, MD, PhD, links two of MJFF’s priority targets, the LRRK2 gene, the greatest genetic contributor to PD discovered to date, with the protein alpha-synuclein, whose clumping appears in the brains of all people with PD.

“Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein – the main component of those protein aggregates that gunk up nerve cells in Parkinson’s patients,” explains Cuervo.

The process targeted in Cuervo’s research, called autophagy, surrounds cellular subunits called lysosomes, which are basically garbage disposals designed to break down and dispel certain unwanted debris from within our cells. Mutations in LRRK2, the study says, seem to cause these lysosomes to lose their ability to get rid of this debris, and specifically, to get rid of alpha-synuclein. This can cause complications: In PD, it’s believed alpha-synuclein build-up is associated with the progressive cell death in the brain that is common to Parkinson’s.

Researchers have more to do to nail down the true nature of the culprit: Scientists still aren’t sure if this alpha-synuclein aggregation might be due to the mutation in the gene itself, or instead a response to the extraneous build-up of this cellular debris. Better understanding what’s at work is crucial to developing potential treatments to counteract the processes at work that might be causing PD. But the ramifications of doing so could be significant: If scientists can understand more about how mutations in LRRK2 lead to this alpha-synuclein build-up and eventually PD, they might be able to create new drugs for everyone with the disease, not just those with the mutation (since everyone with PD experiences alpha-synuclein aggregation).

The good news is, writes Collins, researchers are already hard at work to develop drugs that target autophagy:

“An exciting aspect of this research is that investigators in other fields have identified certain compounds that might be capable of re-booting the chaperone-mediated garbage disposal system, potentially facilitating the breakdown of the toxic alpha-synuclein bundles. Though it will require many more steps to test that idea, this is an intriguing new approach to tackling this crippling disease.”



Parkinson's Research at NEURA funded by Shake It Up & MJFF

Parkinson's Research at NEURA funded by Shake It Up & MJFF