Alpha-synuclein: Back to where it all started
It was early 2007, shortly after I first assumed my position as Associate Professor of Neurology and Neurobiology in the University of Athens Medical School, that I first met A.M., a 62-year-old woman with initial manifestations of Parkinson’s disease. She was tearful and inconsolable when I announced to her that this was indeed the diagnosis, a diagnosis that she had feared for decades, having witnessed 3 of her siblings and her father succumb to an aggressive form of Parkinson’s disease in their 50s. A major concern she had was that her niece, then in her early 40s, seemed to also be developing symptoms of the disease. And, over the years, there were many more close and distant relatives, most residing within the area of the Peloponnese, who came to our attention. Many of them we sougkindredht out ourselves, visiting their homes in rural areas, tracing their family trees and the whereabouts of their relatives.
For these are none-other than descendants of the Greek branch of the famous Contursi kindred, named after a village in Southern Italy. Neurologists Larry Golbe and Roger Duvoisin in New Jersey, working together with Giuseppe Di Orio, had identified these Italian kindred in the late 1980s, noting the autosomal dominant pattern of inheritance, the early age of onset in the mid-40s and the aggressive nature of the disease. Finally, in 1997, through the work of Michalis Polymeropoulos in the laboratory of Bob Nussbaum at the NIH, the responsible gene was identified as the first definitive genetic link to Parkinson’s disease, at an era when neurotoxin exposure was all the rage and the genetic contribution to the disease was considered minimal. Michalis Polymeropoulos is Greek, an MD, a graduate of the Medical School of the University of Patras. At the time of this discovery, he remembered that his Professors in Patras, Aglaia Athanasiadou and Theodoros Papapetropoulos, were following quite a few families in the area of the North-Western Peloponnese with a similar type of autosomal dominant Parkinson’s Disease. Aglaia received a call from Michalis in the middle of the night, asking her to contribute DNA samples from these families, just in case they were related to the Italian families and had the same genetic defect; and, lo and behold, this was the case. This significantly strengthened the idea that the mutation identified, the amino acid Alanine to Threonine substitution in position 53 (A53T) in the SNCA gene, was causal. This was the first clue that alpha-synuclein, the protein encoded by the SNCA gene, was linked to the disease, and the beginning of a new era in Parkinson’s disease research that has dominated the field for the last 28 years, centered on alpha-synuclein as the building block of Lewy Bodies and of other pathological conformations that characterize so-called synucleinopathies. This has culminated in the discovery of the first sensitive and specific biomarker for Lewy Body Diseases through the alpha-synuclein Seeding Amplification Assays (SAAs). But it all started with these families.
This seminal genetic discovery occurred when I was still at Columbia University in New York, working in the lab with Bob Burke and Lloyd Greene, following my training in Neurology. Bob was in fact interested in alpha-synuclein even before the famous Polymeropoulos et al. study was published in 1997, as he had identified the SNCA gene to be regulated in relevant animal models and had noted that it was within the general genetic locus of interest in the Contursi family. As a post-doc in Lloyd’s lab, and later as Faculty in the Movement Disorders Division, I started studying the mechanisms of alpha-synuclein regulation and the toxicity conferred by the A53T mutation in cellular models. And this has been the mainstay of my work in the lab over the years, enriched by the concept of how there may be an aberrant feedback loop between abnormal alpha-synuclein and dysfunctional protein degradation systems, in particular the pathway of Chaperone-Mediated Autophagy; but this is another story.
So, it was a strike of fate perhaps that brought me across A.M. and her family, encountering now in a patient the same mutation I had been studying in cellular models. We have been following A.M. and dozens of other A53T-PD patients over the years and have documented the clinical and imaging features of this rare disease, as well as studied relevant biomarkers related mostly to alpha-synuclein itself and to lysosomal function. Importantly, through the participation of these subjects in the Parkinson’s Progression Markers Initiative (PPMI), we have recently been able to map in detail the very particular course of this disease, and its profound impact on motor and non-motor function, quite unlike idiopathic PD, within the first 8 years of the disease course.
And this is not all: Beware of Greeks bearing mutations! For we have identified another SNCA point mutation, the A30G substitution, linked to Parkinson’s disease in Greek patients. Even though this was first identified in 2021 in families with an autosomal dominant pattern of inheritance through a collaboration with the laboratory of Thomas Gasser, we now have evidence that this mutation can be identified in Greek patients without a clear family history or an early age of onset, suggesting for the first time that an SNCA mutation may occur in the larger community of Parkinson’s disease patients, and should be tested for broadly, at least in cases of Greek origin.
I believe that the importance of these rare genetic synucleinopathy cohorts cannot be overstated. Beyond historical reasons, asymptomatic carriers offer the opportunity to examine the biological disease course in advance of what is known as prodromal phase, to understand when, how and where the disease originates. Cases divergent from the classical course, either asymptomatic at an advanced age, or symptomatic in their 20s or 30s with an even more aggressive or atypical course than usual, offer the opportunity for the discovery of protective or aggravating factors. And, with the advent of the era of safe alpha-synuclein-targeted therapies, these cohorts deserve attention as subjects of small proof-of principle clinical trials, given the manifest link of pathological alpha-synuclein to their disease manifestations and the malignant course. This could be a way through which the Parkinson’s disease community could finally give back something to these families, which have carried the burden of a malignant disease through multiple generations and have illuminated in unprecedented ways the pathogenesis of the idiopathic disease.
Leonidas Stefanis, MD, PhD is Professor of Neurology, National and Kapodistrian University of Athens, and Affiliated Researcher, Biomedical Research Foundation of the Academy of Athens
He has attended most of the past World Parkinson Congresses as a speaker, moderator, or committee member. He is currently the Program Chair for the WPC 2026.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not reflect the opinions or positions of the World Parkinson Coalition®