RG Cellular Resilience Mechanisms and Molecular Modulation
The scientific focus of this research group is on genetic, neurological and immunological diseases in children and adolescents. We investigate the maintenance and adaptation of structure and function (“resilience”) of nerve and immune cells through the evolutionarily conserved signaling pathway autophagy and associated mechanisms of intracellular transport. We are developing translational approaches to understanding and therapy in cellular and animal models that in turn may be transferred to humans in the future.
Focus: Autophagy and intracellular transport
Autophagy (Greek: auto = self, phagos = eat) is an evolutionarily highly conserved signaling pathway for the degradation and recycling of dysfunctional cellular material. Macroautophagy (hereafter autophagy) plays a central role in increased cell turnover in critical phases of life, such as embryological development, perinatal adaptation or further growth and aging processes. The group of autophagy-associated diseases (autophagopathies) is associated with congenital disorders in infection defence, metabolic homeostasis and quality control of proteins and organelles, especially in postmitotic tissues such as neurons. The paradigmatic autophagopathy is the EPG5-associated Vici syndrome with neurodevelopmental disorders, severe combined immunodeficiency and neurodegenerative progression. We are working on a number of genes with regard to their pathomechanisms and genotype-phenotype correlation, e.g., WDR45, SNX14, LYST, RAB3GAP1, RUBCN and the AP3 complex (Figure 1).
Other defects in adjacent intracellular transport show a similar phenotypic spectrum of neurological and immunological disorders with age-related changes in disease progression, e.g., in DYNC1H1-associated disorders.
The focus of our translational work lies on the understanding of basic scientific work at health and the identification of disease mechanisms in celleular and animal models, including human fibroblasts and the nematode Caenorhabditis elegans. In our previous work, we were able to show the biochemical basis of defective autophagy in this disease group. In addition, we were also able to establish new monogenic disorders in intracellular transport with regards to their pathomechanism (PI4K2A).
Dafsari HS, […], Jungbluth H. An update on autophagy disorders. J Inherit Metab Dis. 2025 Jan;48(1):e12798. doi: 10.1002/jimd.12798.
Deneubourg C*, Salimi Dafsari H*, […], Fanto M. Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients. Autophagy. 2025 Feb;21(2):447-459. doi: 10.1080/15548627.2024.2405956.
Dafsari HS*, […], Baur F, Hentrich L, […], Jungbluth H*. Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders. medRxiv 2024.06.12.24308722; doi: 10.1101/2024.06.12.24308722.
Cuccurullo C, […], Salimi Dafsari H, Moller B, […], Coppola A. Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants. Epilepsia. 2024 Sep;65(9):2728-2750. doi: 10.1111/epi.18054.
Möller B, […], Dafsari HS. The expanding clinical and genetic spectrum of DYNC1H1-related disorders. Brain. 2025 Feb 3;148(2):597-612. doi: 10.1093/brain/awae183.
Möller B, Coppola A, Jungbluth H, Dafsari HS. DYNC1H1-Related Disorders. 2024 Mar 21. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 38513047.
Dafsari HS, […], Jungbluth H. EPG5-Related Disorder. 2022 Oct 13. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 36228046.
Dafsari HS*, […], Maroofian R. PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy. Ann Clin Transl Neurol. 2022 Sep;9(9):1345-1358. doi: 10.1002/acn3.51634.
Klionsky DJ, […], Dafsari HS, […], Tong CK. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy. 2021 Jan;17(1):1-382. doi: 10.1080/15548627.2020.1797280.
Further research areas
In the group of rare diseases, there has recently been an exponential increase in new genetic discoveries in neurodevelopmental disorders due to the introduction of high-throughput sequencing in the clinical setting. We are working on the identification and establishment of these rare neurodevelopmental disorders using exome sequencing. This work also extends across scientific networks with collaboration partners at the University College London (UK), Boston Children's Hospital and the University of San Diego (USA).
We have a particular scientific and clinical interest for PUF60-associated diseases, for which we offer an Orphanet-registered specialty clinic and an ERN ITHACA study.
Selected Publications
Ha YJ, Nisal A, […]; Spina Bifida Sequencing Consortium; Kim S, Gleeson JG. The contribution of de novo coding mutations to meningomyelocele. Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08676-x.
Nakamura Y, […], Dafsari HS, […], Saitoh S. Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia. Brain. 2024 Nov 4;147(11):3949-3967. doi: 10.1093/brain/awae185.
Baum E, […], Dafsari HS. Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders. Int J Mol Sci. 2024 Feb 8;25(4):2053. doi: 10.3390/ijms25042053.
Hentrich L, […], Dafsari HS. Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy. Genes (Basel). 2023 Sep 25;14(10):1860. doi: 10.3390/genes14101860.
Saffari A, […], Dafsari HS, […], Maroofian R. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders. Brain. 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039.
The immune system plays a crucial role in the development, function and regeneration of the nervous system. Immunoregulatory disorders can have profound effects on neuronal resilience and defence against pathogens.
Primary immunodeficiencies (PID) are monogenic disorders of the immune system that are often associated with neuroinflammatory and neurodegenerative symptoms. We are working on autophagolysosomal processes (LYST-associated Chediak-Higashi syndrome) and IL6 signal transduction (LIFR-associated Stüve-Wiedemann syndrome).
Acquired inflammatory diseases are caused by an impaired immune response against the central nervous system (CNS). Immune dysregulation acquired during childhood may also lead to inflammatory neurodegeneration, e.g. in MOGAD/MS spectrum diseases or histiocytosis.
We investigate acute parainfectious diseases such as acute disseminated encephalomyelitis (ADEM) and postviral pathomechanisms of autoimmune-mediated demyelination of the CNS through T-cell and B-cell-driven inflammation.
We have a particular scientific and clinical interest in postviral syndromes with chronic inflammation, dysregulation of the autonomic and central nervous system and mitochondrial dysfunction. We are currently participating as a study center in two projects (PEDNET-LC and COVYOUTHdata, funded by the Federal Ministry of Health).
Selected Publications
Bernardi K, [...], Dafsari HS. Novel Clinical and Molecular Findings in Rare Histiocytotic Disorders May Mimic Inflammatory CNS Disorders. Neuropediatrics 2024; 55(S 01): S1-S25. doi: 10.1055/s-0044-1791901
Körner RW, Bansemir OY, Franke R, Sturm J, Dafsari HS. Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents. Children (Basel). 2023 Sep 25;10(10):1598. doi: 10.3390/children10101598.
Targets for biochemical neuromodulation are increasingly being recognized while the pathomechanisms of neurological diseases are identified in cellular and animal models.
We already offer approved molecular therapies based on antisense oligonucleotides (ASOs) for spinal muscular atrophy (SMA) in the clinical setting of the Neuromuscular Center at the Children's Hospital. We are currently working on the continuous development of new ASOs for other diseases. Furthermore, we are also working on the modulation of metabolic targets in dysfunctional signaling pathways using molecular small compound therapy, e.g. treatment with vitamin B12/cobalamin or vitamin B9/folic acid.
Selected Publications
Cheerie D, […], Dafsari HS, […], Schober E, […], Lauffer MC; N=1 Collaborative. Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments. Am J Hum Genet. 2025 Mar 21:S0002-9297(25)00064-3. doi: 10.1016/j.ajhg.2025.02.017.
Vong KI, […]; Spina Bifida Sequencing Consortium‡; […], Gleeson JG. Risk of meningomyelocele mediated by the common 22q11.2 deletion. Science. 2024 May 3;384(6695):584-590. doi: 10.1126/science.adl1624.
Funding
PEDNET-LC: Total duration 2024 - 2028 (German Federal Ministry of Health)
COVYOUTHdata: Total duration 2025 - 2028 (German Federal Ministry of Health)
Team
Emily Baum, cand. med.
Franciska Baur, physician
Rosa Franke, cand. med.
Antonia Gehrckens, cand. med.
Lea Hentrich, cand. med.
Dr. Robert Körner, study physician in the PEDNET-LC project
Birk Möller, cand. med. med.
Madeleine Schmidt, physician
Helena Schönrade, cand. med.
Juliane Schuler, cand. med.
Julius Sturm, cand. med.
Marieke Toepffer, cand. med.
Lea Tollmann, cand. med.
Maxi Leona Wiese, physician
We welcome unsolicited applications for clinical or laboratory-based doctorates for physicians (Dr.), psychologists or natural scientists (PhD) with a CV, letter of motivation and an email to hormos.dafsari@uk-koeln.de.