At the heart of much research into Parkinson's, both its causes and new forms of treatment, is a type of brain protein called alpha-synuclein. This is known to play an important role in the movement of vesicle structures that transport materials in and around cells, but new research has found it is in fact leading a "double life," impacting on gene expression in a way that opens up new possibilities for treatment.
The reason alpha-synuclein receives the attention it does in Parkinson's disease research is because the protein has an ability to misfold and accumulate into toxic clumps that cause damage to important brain cells. Experimental therapies designed to target this type of protein dysfunction have shown exciting potential, such as engineered peptides and compounds derived from sharks.
Studies that deepen our understanding of the protein's behavior, meanwhile, have helped us understand the potential origins of Parkinson's, including the possibilities that it begins in the gut and could be an autoimmune disease. This new study, conducted by scientists at Brigham and Women’s Hospital, MIT and Harvard, sheds further light on the functions of alpha-synuclein, and began with investigations on yeast systems and fruit fly models.
The team's experiments revealed that the same part of the alpha-synuclein protein that binds with vesicles also binds with cellular machinery called "P-body" structures, which help regulate gene expression via messenger RNA (mRNA). These findings were validated through experiments on patient-derived neurons and neurons generated from induced pluripotent stem cells. The latter featured alpha-synuclein gene mutations that altered the composition and function of the P-body structures, and led to abnormal regulation of the mRNA.
“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,” said corresponding author Vikram Khurana. “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 our study suggests alpha-synuclein is leading a double life.”
The scientists saw the same mechanisms at play in post-mortem tissue samples from Parkinson's patients, and the findings were also supported by genetic analysis indicating that patients with mutations in the P-body genes appeared at higher risk of developing the disease. In influencing gene expression as well as vesicle transport, the scientists see alpha-synuclein as a type of "toggle switch" responsible for two distinct functions, and say that there is an imbalance in its duties in disease states. More work is needed to understand these behaviors and translate them into a clinical treatment, however, with the scientists now looking to ascertain how much the pathway contributes to progression of the disease.
“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,” said lead author Erinc Hallacli. “This paper provides important information to fill our knowledge gaps about this protein, which may be beneficial for clinical translation.”
The research was published in the journal Cell.
Source: Brigham and Women’s Hospital
