Dafsari, Hormos C - CAP 42

1. Define how EPG5 gene dosage shapes neuronal resilience. In patient-derived iPSC-neuron and long-term brain-organoid models, we examine autophagosome-lysosome fusion, mitophagy and cell-type-specific vulnerability, with particular emphasis on dopaminergic neurons.

2. Resolve the autophagy-mitochondria-inflammation axis over time. We investigate the timing of defective organelle clearance leading to mitochondrial dysfunction, mtDNA leakage, cGAS-STING/TBK1 activation and the integrated stress response, and how these events relate to accumulation of alpha-synuclein, tau and amyloid-associated pathology.

3. Develop mechanism-guided therapies. We conceive and optimize splice-switching antisense oligonucleotides (ASOs) and small-molecule splicing and pathway modulators, then test whether early intervention prevents disease trajectories and whether later intervention can restore autophagic flux and attenuate established pathology.

Together, these aims serve as a human experimental platform for collaborative target validation, biomarker studies and preclinical therapeutic testing across autophagy-related neurodevelopmental and neurodegenerative disorders.

Neurodegenerative disorders represent a major and growing clinical burden, yet mechanisms determining individual vulnerability and timing of onset remain insufficiently understood. Autophagy impairment is a modifiable contributor as it affects proteostasis, organellar health and integrated stress signalling. Our work programme provides a clinically anchored route to mechanism by leveraging EPG5 as a human gene-dosage model that bridges rare childhood-onset neurogenetic disease and more widespread adult-onset neurodegeneration. This rare-to-common strategy is founded in monogenic models, fundamental pathomechanisms and established biomarkers to enable precision-medicine in patients and families.

Paradigmatic metabolic diseases in childhood mostly present with multisystem disorders, particularly in patients with innate errors in autophagy and intracellular trafficking that show a wide disease spectrum from neurodevelopmental disorders, neurodegenerative disease courses, hypopigmentation and immune deficiency. This research group is embedded offering specialized care at the Division of Pediatric Neurology with its neurogenetic, neuromuscular, immunology and metabolic clinics, including translational pipelines deeply embedded into the translational research campus with the Center for Rare Syndromal Diseases and Center for Gene and Cell Therapy at the University of Cologne. 

The project seeks targeted treatments that correct defective RNA processing or restore cellular clearance rather than suppressing a single downstream marker. Antisense oligonucleotides (ASOs) already have regulatory and clinical precedents in neurological disease, making them a pragmatic route from molecular diagnosis to precision therapy.