By Erinc Hallacli and Vikram Khurana

Within a cell, proteins are made, perform their function(s) and are degraded to recycle their amino acids. When cells cannot successfully execute this protein-recycling efficiently or a particular protein becomes resistant to degradation (for instance, the protein is mutated or aging diminishes a cell’s degradative capacity), proteins can accumulate, misfold and form large aggregates in the cell. One such protein is alpha-synuclein. In Parkinson’s Disease (PD), the most notable markers in a patient’s brain postmortem are “clumps” (aggregates) enriched in this protein that accumulate in neurons. Not surprisingly, the research community is intensely interested in the role of alpha-synuclein in the pathogenesis of PD.

A known property of alpha-synuclein protein is its ability to bind to the lipid surface of cellular “vesicles” in a reversible manner. These vesicles are small spherical structures that traffic protein cargos inside the cell. There is strong evidence that a perturbed relationship of alpha-synuclein to the membrane of these vesicles leads to a cellular “traffic jam” in neurons in PD patient brains. Some cell types like dopamine-secreting neurons may be particularly susceptible to these effects.

Mysteriously, however, alpha-synuclein spends much of its time off these membranes, unanchored in the cytoplasm of cells. What it does when it’s not bound to membranes has been a puzzling open question in the field. In this study, we discovered that alpha-synuclein binds to and regulates cytosolic enzyme complexes called Processing bodies. Processing bodies are central hubs for mRNAs. If DNA is the textbook for a cell, then mRNAs read that book and write it into our proteins. P-bodies host critical enzymes for mRNA quality control, modification, and decay. In other works, P-bodies are quite important for regulating how are genes are read out into proteins. We have found that alpha-synuclein binds a particular set of enzymes within P-bodies responsible for removing the “cap” of mRNAs and their subsequent degradation – the so-called “decapping module”. We showed that in neurons derived from patients that have extra copies of synuclein (leading to early onset PD) there is altered stability of mRNA levels and a compromised decapping module. We show something similar is happening in PD patient brains.

The Double Life of Alpha-Synuclein. Original Artwork by Gergana Petrova

Curiously, alpha-synuclein uses the same patch of amino-acids to bind either to vesicle membranes or the decapping module, suggesting the two functions regulate each other – an unexpected “double life” for alpha-synuclein. Furthermore, by probing human genetics data, we showed that mutations in P-body genes accumulate in PD patients more than healthy controls, so this machinery looks to be important not just for alpha-synuclein function but for susceptibility to disease.

Our results have implications for PD therapy. More work is needed but P-bodies may reflect a new molecular vulnerability pathway for alpha-synuclein mediated cell damage. Our work implies that the fine balance between membrane and P-body bound alpha-synuclein needs to be carefully considered for any therapeutic interventions that target alpha-synuclein.

Erinc Hallacli is an instructor of Neurology in Harvard Medical School and Brigham and Women’s Hospital.

Vikram Khurana is Chief of the Division of Movement Disorders at Brigham and Women’s Hospital and Harvard Medical School. He is Principal Faculty at the Harvard Stem Cell Institute, and an Associate Member of the Broad Institute of Harvard and MIT.

Learn more in the original research article:
The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability.
Hallacli E, Kayatekin C, Nazeen S, Wang XH, Sheinkopf Z, Sathyakumar S, Sarkar S, Jiang X, Dong X, Di Maio R, Wang W, Keeney MT, Felsky D, Sandoe J, Vahdatshoar A, Udeshi ND, Mani DR, Carr SA, Lindquist S, De Jager PL, Bartel DP, Myers CL, Greenamyre JT, Feany MB, Sunyaev SR, Chung CY, Khurana V.  Cell. 2022 Jun 9;185(12):2035-2056.e33.