A novel function for alpha-synuclein, a well-known protein marker for Parkinson’s disease, has been discovered, with potential for treatment.

Parkinson’s disease (PD) is characterized by the buildup of the protein alpha-synuclein in the brain. Since more than two decades ago, alpha-synuclein has been the primary focus of PD researchers, doctors, and pharmaceutical companies.

However, the role of alpha-synuclein remains unknown.

A new study led by researchers at Brigham and Women’s Hospital, Harvard Stem Cell Institute, and the Broad Institute of Harvard and MIT sheds new light on the role of alpha-synuclein, revealing a new function for the protein that could be relevant to Parkinson’s disease and other neurological disorders.

The findings were reported in the journal Cell.

“Our study offers new insights into a protein that is known to be at the center of the development of Parkinson’s disease and related disorders,” says corresponding author Vikram Khurana, adding “this is a protein that is being targeted by current therapeutics, but its function has been elusive. Traditionally, alpha-synuclein has been thought to play a role in binding to the cell membrane and transporting structures known as vesicles.”

But, according to the study authors, “alpha-synuclein is leading a double life”.

Initial leads for Khurana and colleagues came from yeast and fruit fly models of alpha-synuclein toxicity, which were backed up by research on human cells, patient-derived neurons, and human genetics.

The researchers discovered that the same component of the alpha-synuclein protein that interacts with vesicles also binds to “P-body” structures, cell machinery that controls gene expression via messenger RNAs (mRNAs).

In neurons obtained from induced pluripotent stem cells that were created from PD patients with alpha-synuclein gene mutations, the physiologic shape and function of the P-body were lost, and mRNA regulation was aberrant.

The same thing happened in tissue samples from patients’ postmortem brains. Patients that accumulate mutations in P-body genes appeared to be at increased risk for Parkinson’s disease, according to human genetic analysis.

According to scientists, alpha-synuclein acts as a “toggle switch” that controls two distinct functions: vesicle transport and gene expression. The balance is disrupted in illness conditions.

The findings could have consequences for the development of Parkinson’s disease treatments. The authors state that more research is needed to determine which components of the P-body machinery are the ideal targets for therapeutic intervention.

Ongoing genetic research is attempting to determine which people would benefit most from such an intervention, as well as how much this newly found pathway contributes to disease risk and progression in PD patients in general.

“If we want to be able to develop treatments that target alpha-synuclein, we need to understand what this protein does and the potential consequences of reducing its level or activity,” adds the main scientist Erinc Hallacli.

“This paper provides important information to fill our knowledge gaps about this protein, which may be beneficial for clinical translation,” says the author.

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