Xanthopoulos, K. | bioRxiv Science

bioRxiv2025

Genetic affinities between an ancient Greek colony and its metropolis: the case of Amvrakia in western Greece

BackgroundDuring the Ancient Greek colonization, Corinth established a stable network of economic and political ties, by founding colonies connecting southern Greece with the mainland of Epirus and reaching as far as the east Adriatic coast. Amvrakia, one of the main Corinthian colonies founded during the 7th century BCE, was characterized by its strong dependence on its metropolis. Here, we aim to investigate the genetic relationships between the Corinthian metropolis and the Amvrakia colony, the contribution of the local population to the founding genetic pool, as well as the demography of Amvrakia in subsequent periods. ResultsDuring its foundation in the Archaic period, Amvrakia appears to have been shaped by genetic influences from at least two different sources. The first source migrated from the Corinth territory, represented by the Archaic Tenea population and is supported via an Identity By Descent (IBD) analysis. The second source shows a direct ancestry from Late Bronze Age (LBA) / Iron Age Greece, including a local LBA population represented by the Ammotopos site located in close proximity to Amvrakia, as shown by a plethora of independent population genomics analyses. During the subsequent Classical and Hellenistic periods, the population of Amvrakia appears to have slightly differentiated, yet evidence of genetic continuity over time is observed. ConclusionsThe migration of Corinthians to Amvrakia contributed to the initial genetic pool of the colony along with the local genetic pool, indicating that the Corinthian colonization included both genetic and cultural transmission between the metropolis and its colony.

evolutionary biology↗

bioRxiv2025

Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1 protein. This expansion is thought to be responsible for the gradual aggregation of the mutant protein, which is associated with increased cytotoxicity and neuronal cell death. Apart from the polyQ tract, other domains in ATXN1 are also involved in the initial events of protein aggregation such as a dimerization domain that promotes protein oligomerization. ATXN1 interacts with various proteins; among them, MED15 that significantly enhances the aggregation of the polyQ-expanded protein. Therefore, we set to identify the interaction site between ATXN1 and MED15 and assess whether its chemical targeting would affect polyQ protein aggregation. First, we predicted the structure of ATXN1 and MED15 and simulated their interaction. We experimentally validated that amino acids (aa) 99-163 of ATXN1 and aa548-665 of MED15 are critical for this protein-protein interaction (PPI). We also show that the aa99-163 domain in ATXN1 is involved in the dimerization of the mutant isoform. Targeting this domain with a chemical compound identified through virtual screening (Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with MED15 and the dimerization of polyQ-expanded ATXN1. These results strengthen our assumption that the aa99-163 domain of ATXN1 may be involved in polyQ protein aggregation and highlight compound 5755483 as a potent first-in-class therapeutic agent for SCA1.

neuroscience↗