“The new finding gives us a clue as to where to intervene,” said Lipton, who holds a joint position at the University of California, San Diego, School of Medicine, where he is a practicing clinical neurologist involved in the care of Parkinson’s patients.
The study was published today in the journal Cell Reports.
‘PINK-SNO Man’ Implicated in Parkinson’s
The SNO reaction attaches a nitric oxide-like molecule to protein called PINK1, where the molecule attaches to a building block on PINK1 called a cysteine residue. This changes PINK1’s activity–and its ability to do its job.
Since Lipton’s group co-discovered the SNO reaction some 20 years ago, scientists have linked the reaction to protein misfolding and nerve cell damage in cases of Alzheimer’s, Huntington’s, amyotrophic lateral sclerosis (ALS/Lou Gehrig’s disease) and Parkinson’s disease, as well as heart/cardiovascular disease and cancer.
In the new study, Lipton and his colleagues used human stem cell and mouse models to show exactly how SNO can trigger cell death in Parkinson’s disease. They found that when SNO modifies PINK1, nerve cells cannot recruit another protein called Parkin to get rid of damaged mitochondria.
“Mitochondria are the energy powerhouses of the cell,” explained Lipton. Because neurons need a lot of energy, Lipton said, it is especially crucial for them to use only healthy mitochondria and get rid of the damaged ones. Mitochondria can be damaged as people age and cells experience various forms of stress, and it is the job of PINK1 to help trigger a process called mitophagy to remove those dysfunctional mitochondria.
Previous studies had shown that inherited mutations to the gene that codes for PINK1 can stop a person from making working versions of the protein. This means their neurons cannot clear damaged mitochondria, and those cells eventually die–which can cause Parkinson’s.
The SNO reaction seems to cause this same problem, but it is not inherited. Instead, cells start “SNO-ing” proteins when they get overwhelmed by reactive nitrogen molecules. “The quantities of these reactive chemical species get so high that cells start SNO-ing proteins, like PINK1, that would normally not be SNO-ed,” said Lipton. The researchers call this the PINK-SNO complex, or a “PINK-SNO man.”
