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9th Edition of International Conference on

Neurology and Neurological Disorders

June 20-22, 2024 | Paris, France

Neurology 2022

Andreas Till

Speaker at Neurology and Neurological Disorders 2022 - Andreas Till
University of Bonn, Germany
Title : In vitro modelling of brain development and neurodegenerative diseases

Abstract:

Given the complex etiopathology of neurodegenerative diseases and the limited access to vital human brain cells as suitable research platform, there is an increasing demand of innovative human-specific model systems that help elucidating the causative mechanisms of these disorder and open the avenues for novel prevention and/or treatment strategies. The advent of cell reprogramming has enabled the generation of induced pluripotent stem cells (iPSCs) from patient fibroblasts or blood cells and their subsequent differentiation into tissue-specific cells, including neurons and glia. This approach in combination with in vitro genome-editing technology is suitable to recapitulate disease-specific phenotypes but also neurodevelopmental aspects in classical cell culture paradigms and thus represents an invaluable asset for developmental research, disease modelling and drug validation in the framework of personalized medicine.

Here we demonstrate how in vitro modelling of neurodevelopment and neurodegeneration in classical two-dimensional and 3D model systems may unveil underlying causative mechanisms and target pathways. First, we demonstrate that the cytoprotective NRF2 signaling pathway is upregulated and activated during neuronal differentiation from neural stem cells to maturing neural populations. We continue to show how this pathway is regulated and able to protect neural populations from environmental insults, e.g. oxidative stress, during development. Next, using iPSC-derived dopaminergic neurons from a Parkinson’s Disease (PD) patient carrying the causative LRRK2 G2019S mutation, we demonstrate that mutant carrier cells display defects in homeostatic turnover of mitochondria (‘mitophagy’) as early as at day 8 of differentiation. These data pinpoint one important causative mechanism in the pathology of PD, i.e. quality control of mitochondria, and emphasize the vital role of mitophagy regulation during early steps of neuronal development. Moreover, we asked which subcellular pathways contribute to formation of neuronal intranuclear inclusions (NIIs) of mutant Ataxin-3 protein in an iPSC model of polyglutamine disease (spinocerebellar ataxia type 3/SCA3). Inhibition of autophagy (an essential lysosomal degradation system) resulted in a significant increase of NIIs in the susceptible cell population, and the build-up of NIIs could be abated by pharmacological upregulation of autophagic flux. As outlook, we present our approach on how to dissect the connection between diet, the gut microbiome composition, brain circuitry and manifestation of metabolic diseases such as obesity and its comorbidities (including dementia) using a translational approach in combination with in vitro model systems.

In summary, our work emphasizes the usability of innovative in vitro models for assessment of development, disease pathways and even organ crosstalk.
 

What will audience learn from your presentation?

The audience will learn

  • which in vitro model systems are nowadays available to study disease mechanisms in the dish
  • which histological and molecular features could be used in the clinic to interpret pathological findings
  • which shared cellular and molecular events underly the pathogenesis of neurodegenerative diseases
  • how preclinical drug screening can be performed on authentic human cells

Biography:

Andreas Till is an experienced and dedicated cell biologist whose research focuses on cellular stress pathways associated with (and potentially mediating) human diseases. He received his PhD at the University of Kiel in Northern Germany where he studied proinflammatory signaling and pathogen detection in the context of chronic inflammatory diseases. After receiving a research fellowship by the German Research Foundation (DFG), he worked for three years in the group of Suresh Subramani at the University of California San Diego (UCSD). Here he focused on molecular mechanisms that regulate selective autophagy, a vital subcellular degradation pathway involved in various diseases, including neurodegeneration and infection. Next, he joined the University of Bonn, Germany, as team leader and lecturer for Molecular Biomedicine. Besides his academic career, he also worked as senior scientist for the Life&Brain GmbH, a University – associated biotech company dedicated to applied research in the context of Central Nervous System disorders. In January 2020, he was appointed lab head in the Medical Clinic I, section for Metabolic Diseases.  Over the last years, Andreas Till has specialized on in vitro cell models for human diseases, focusing on cellular stress pathways such as antioxidative responses, inflammatory signaling, autophagy and metabolic reprogramming. In particular, he was involved in development and application of cellular reporter systems for elucidating pathophysiological mechanisms underlying neurodegenerative, infectious and metabolic diseases. Very recent projects aim to elucidate the interconnection between diet, the gut microbiome and neural circuits to regulate energy and nutrient homeostasis in the context of obesity and its comorbidities. Dr. Till has published more than 60 papers, organized scientific workshops and presented his research at several international conferences in Europe, USA, Japan and China.

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