A. Nazlı Başak, earned her BS degree in Chemistry from the University of Göttingen, Germany, and completed her MSc and PhD programs in Molecular Biology and Genetics at the Max Planck Institute (MPI) for Experimental Medicine in Göttingen under the scientific guidance of Prof. Friedrich Cramer on nucleic acid biochemistry, tertiary structure of the tRNA molecule and protein biosynthesis mechanisms. After three years of postdoctoral research work and five years of research assistance at MPI in Göttingen, she returned to Turkey.
Dr. Başak’s career at Boğaziçi University in Istanbul started with the establishment of DNA techniques used in the early detection and prevention of hereditary blood disorders. She was instrumental in the establishment of a fully equipped molecular biology and genetics laboratory for the first time in Turkey. Her research laboratory at Boğaziçi University, in collaboration with the Turkish Ministry of Health, played a major role in the implication of a comprehensive nation-wide prevention program for the early prenatal diagnosis of thalassemias and abnormal hemoglobins, based on DNA analysis, in Turkey.
In 1990s Nazli Başak’s research interest shifted from monogenic blood diseases towards complex brain disorders. Dr. Başak’s current research agenda focuses on neurodegenerative disease genetics. With her interest in mechanisms giving rise to neurodegeneration, she was appointed in 2005 as the director of NDAL (Neurodegeneration Research Laboratory), established by the prestigious Suna and İnan Kıraç Foundation at Boğaziçi University.
NDAL regularly hosts the prestigious Suna Kıraç Conferences on Neurodegeneration Istanbul in collaboration with UMass and Harvard Medical Schools and the Suna Kıraç Workshops on Genetic Models of Neurodegenerative Disease with Brown University’s Carney Institute for Brain Science. The laboratory has a nationwide recognition as a center of excellence in the molecular diagnosis of common and rare neurological diseases in Turkey. The translocation of NDAL to Koç University’s Medical School in 2018, enabling a tighter interaction with specialist clinicians and hospitals, enhanced the visibility and efficiency of NDAL, exponentially increasing the number of international collaborations and transnational consortia projects. Currently, the lab is the turkish partner of Project MinE, the coordinator of the European EJP-ND Project PROSPAX on spastic ataxias, an active member of the ASAP/GP2 initiative on Parkinson’ dlsease and was recently awarded an IDRC Research Grant on ALS-microbiome interaction, partnering with the University of Calgary, Canada and Israel’s Weizmann Institute in Rehovot. NDAL is involved in many other consortia on neurodegenerative disease biology, like the RFC1 Consortium, Solve-RD Research Project and the Genesis Platform.
The Complex Architecture of ALS in Turkey
The last decade has seen an exponential progress in data output, based on advances in genetics, genomics and on large international collaborations. Consequently, our knowledge of the genetic factors behind ALS has improved in an unparalleled fashion and the scientific scenario of ALS has dramatically changed. Today, the disease is accepted to be part of a continuum with other neurological diseases and a crossroads between genetic, neurometabolic and environmental factors.
ALS genetic research has been largely focused on populations of European ancestry and attention has only recently shifted to other ethnicities. To the best of our knowledge, this is the largest and most systematic study performed in Turkey so far, a large country with a young population. As opposed to European countries in which family sizes steadily decreased in the last 50 years, Turkey still has a high birth rate with large kindreds and many offspring. Especially in the rural parts of the country, high consanguinity, consisting of mainly first cousin marriages is part of the culture and rather the rule than the exception. With its wealthy historical background and unique geographical position between three continents, the Anatolian Peninsula is a rich genetic pool with a high ethnic heterogeneity on one hand and inbred on the other.
A total of 2,320 ALS patients recruited from specialist centers across Turkey in the last 20 years were analysed within the scope of this study, adopting a combination of conventional and NGS approaches; 501 of these are familial cases (21.5%) and 1819 are sporadic patients (78.5%). The four major ALS genes, C9ORF72, SOD1, TARDBP, FUS contribute to 35% of fALS and 6% of sALS. Analysis of pathogenic exonic variants obtained from WES and WGS data increases these numbers to 45% in fALS and 10% in sALS.
Apart from classical ALS genes, WES revealed variants in rare genes associated with diverse motor neuron phenotypes with upper or lower motor neuron predominance pointing to a great heterogeneity with presently 53 genes identified in the ALS cohort under study. Locus and allelic heterogeneities, genetic pleiotropy, variable penetrance, genetic discordance, and oligogenic etiology contribute to the complex genetic landscape of ALS in Turkey. Moreover, the variability and fluidity of observed phenotypes, not only in ALS, but among all neurodegenerative diseases warrant a rethinking of the traditional disease taxonomy. Under the surface of the disparate clinical, syndromic and diagnostic classification, hide not only shared genes and phenotypes, but also common mechanisms and pathways.
