Un graphique illustre les “deux visages de l’alpha-synucléine” et la transition entre les états normaux (en haut, machines moléculaires organisées sur une grille bien définie) et les états pathologiques dans lesquels il y a une perturbation de la membrane, des interactions protéiques altérées et une localisation (en bas, machines chaotiques et perturbées, ton plus sombre). Crédit : Œuvre d’art de Gergana Petrova
Des chercheurs ont découvert une nouvelle fonction pour l’alpha-synucléine, un marqueur protéique bien connu de la maladie de Parkinson, avec un intérêt pour le traitement de cette maladie.
Lorsque de nombreuses personnes pensent à la maladie de Parkinson, elles l’associent à Michael J. Fox. Peut-être se distingue-t-il simplement parce qu’il a été diagnostiqué à un si jeune âge, car la maladie de Parkinson est en fait relativement courante. En fait, près d’un million d’Américains en sont atteints, et environ 60 000 autres sont diagnostiqués chaque année, selon la Fondation Parkinson, ainsi que d’autres personnes notables comme George H.W. Bush, Muhammad Ali, Billy Connolly, Neil Diamond et Billy Graham.
Heureusement, les scientifiques travaillent d’arrache-pied pour comprendre la maladie, afin de mettre au point des cures et des traitements. De nouveaux progrès ont été réalisés sur ce front grâce à de nouvelles recherches qui ont révélé des informations essentielles sur une protéine clé.
L’une des caractéristiques de la maladie de Parkinson (MP) est l’accumulation dans le cerveau d’une protéine appelée alpha-synucléine. Depuis plus de deux décennies, l’alpha-synucléine est au centre de l’attention des chercheurs, des cliniciens et des fabricants de médicaments qui s’intéressent à la maladie de Parkinson. Mais la fonction de l’alpha-synucléine n’est pas bien comprise. Une nouvelle étude menée par des chercheurs du Brigham and Women’s Hospital, du Harvard Stem Cell Institute et du Broad Institute de Harvard et MIT shines new light on the role of alpha-synuclein, uncovering a new function for the protein with relevance for PD and related conditions. Findings will be published today (June 9, 2022) 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,” said corresponding author Vikram Khurana, MD, PhD, chief of the Division of Movement Disorders within the Department of Neurology at the Brigham and Harvard Medical School, and a principal investigator within the Ann Romney Center for Neurologic Diseases at the Brigham. “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.”
Khurana and colleagues’ initial leads came from yeast and fruit fly models of alpha-synuclein toxicity and were substantiated through studies of human cells, patient-derived neurons, and human genetics. The team found that the very same part of the alpha-synuclein protein that interacts with vesicles also binds to “P-body” structures, machinery in the cell that regulates the expression of genes through messenger RNAs (mRNAs). In induced pluripotent stem cell-derived neurons generated from PD patients with alpha-synuclein gene mutations, the physiologic structure and function of the P-body was lost, and mRNAs were abnormally regulated. The same occurred in tissue samples from postmortem brains from patients. Human genetic analyses supported the disease-relevance of these findings: patients who accumulate mutations in P-body genes appeared to be at higher risk for PD.
The authors describe alpha-synuclein as a “toggle switch” that regulates two very distinct functions: transport of vesicles and gene expression. In disease states, the balance is broken. The findings have potential implications for development of treatments for PD. The authors note that more clarity is needed on which of the P-body machinery components might be the best targets for a therapeutic intervention. Ongoing genetic studies aim to identify which patients might be best suited for such an intervention, and how much this newly discovered pathway contributes to risk of the disease and disease progression in PD patients at large.
“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, PhD, of the Department of Neurology and the Ann Romney Center for Neurologic Diseases at the Brigham. “This paper provides important information to fill our knowledge gaps about this protein, which may be beneficial for clinical translation.”
Reference: “The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability” 9 June 2022, Cell.
DOI: 10.1016/j.cell.2022.05.008
Funding: Khurana is a NYSCF Stem Cell Robertson Investigator and an investigator of the Aligning Science Across Parkinson’s Initiative. He is a George C. Cotzias Fellow of the American Parkinson’s Disease Association. This work was also supported by the Brigham Research Institute Director’s Transformative Award, Department of Defense (W81XWH-19-1-0695), Human Frontier Science Program (LT000717/2015-L) and the National Institutes of Health (R21NS112858, R21NS112858 and R01NS109209). Additional funding support was provided by Alzheimer’s Research UK (ARUK), the Biomarkers Across Neurodegenerative Diseases Grant from the Alzheimer’s Association, Koerner New Scientist Program from the Koerner Family Foundation, Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Weston Brain Institute (Weston) (BAND-19-615151).
Disclosures: Khurana is a co-founder of and senior advisor to Dacapo Brainscience and Yumanity Therapeutics, companies focused on central nervous system diseases. Co-authors Chee Yeun Chung and Xin Jiang contributed to this work as employees of Yumanity Therapeutics.
