Accumulated alpha-synuclein (αS) is a major component of Lewy bodies in Parkinson’s disease and other neurodegenerative disorders. Normally, αS binds to cell membranes and regulates the transportation of vesicles.
Vikram Khurana, MD, PhD, chief of the Division of Movement Disorders in the Department of Neurology at Brigham and Women’s Hospital, and colleagues have discovered an additional function of αS—it modulates the stability of messenger RNA, thereby regulating gene expression. In Cell, the researchers explain that their finding has implications for understanding normal cellular physiology and developing therapies for Parkinson’s disease and related disorders.
In yeast and fruit fly models, the researchers discovered that toxic accumulation of αS is associated with mRNA degradation. They observed interactions between αS and a core set of proteins that reside in P-bodies—structures in eukaryotic cells that regulate the expression of genes through mRNA.
Those proteins (Edc4, Dcp1, Dcp2, Xrn1, and Edc3) were involved in the decapping and degradation of mRNA. The interactions occurred on the same region of αS, the N-terminus, which interacts with vesicles.
Substantiation in Human Cells
The researchers investigated neurons derived from pluripotent stem cells of patients with Parkinson’s disease who had αS gene mutations. αS interacted more strongly with Edc4 than with other P-body components. When neurons expressed pathologic levels of αS or were seeded with αS fibrils, interactions between Edc4 and αS increased. These associations disrupted other normal P-body processes, and mRNAs were globally stabilized.
A similar phenomenon was observed in postmortem brain tissue from patients with Parkinson’s disease. αS buildup and increasing signs of disease severity were associated with greater disruptions to mRNA breakdown.
Human genetic analyses supported the relevance of these findings—accumulation of mutations in P-body genes seemed to be linked to a higher risk of Parkinson’s disease.
New Directions for Research
Thus, αS regulates two very distinct functions: transport of vesicles and gene expression. In Parkinson’s disease and related disease states, the balance between the two is disturbed, and one or more of the P-body components might be a good target for therapeutic intervention.
Genetic research is underway at the Brigham to identify which patients would be best suited for such an intervention and how strongly the newly discovered pathway drives vulnerability to Parkinson’s disease and the progression of the disease.
Altered αS interactions and pathology might directly impact other key cytosolic functions, including mRNA metabolism. Therefore, these findings also open up new ways to consider the role of αS in health and disease, in different cellular compartments and in different cell types.