Zempel, Hans - CAP 28
Molecular Mechanisms and Gene Therapy approaches for Genetic and Sporadic Neurodegenerative Diseases
Dr. Dr. Hans Zempel
Institute of Human Genetics
CMMC - PI - CAP 28
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Institute of Human Genetics
Robert-Koch-Str. 21
50931 Cologne
Introduction
Frontotemporal Dementia (FTD) and variants thereof, such as Progressive Supranuclear Palsy (PSP), Picks disease (PiD) and Corticobasal Degeneration (CBD) can be classified as ageing-associated taupathies. These taupathies, as well as Alzheimer’s disease (AD), the most prevalent form of dementia, and other TAU and mitochondria related dementia-causing syndromes are devastating disorders that impose a huge burden on society. Genetic variants, splicing defects and pathological axodendritic distribution of the protein TAU cause or significantly contribute to these diseases. Understanding the neurobiological, cellular and molecular mechanisms underlying TAU physiology in disease relevant human cells is crucial for developing successful therapeutic approaches for AD and associated diseases.
Our recently established junior research group: “Functional Genetics of Neurodegeneration and Neurological Disease” currently works on the elucidation of pathomechanisms of genetic and sporadic forms of tauopathies, including AD and mitochondriopathies. By better understanding the molecular disease mechanisms, we strive to identify and test novel therapeutic approaches for these currently incurable diseases. As model systems, we focus on human iPSC-derived neurons (iNs), TAU-humanized mice and primary neurons derrived from these, as well as several other cell types (e.g. patient-derived primary fibroblasts). We use lentiviruses (LV), state of the art microscopy (i.a. calcium imaging, photoconversion/optogenetics, STED-nanoscopy) and omics approaches ((sc)RNAseq and proteomics) to elucidate disease mechanisms and test therapeutic approaches in disease-relevant human neurons and in TAU-humanized mice.
Figure 1
Clinical Relevance
Understanding molecular disease mechanisms is crucial for targeted development of therapies for above mentioned difficult-to-treat neurogenetic and neurodegenerative diseases. We not only dissect pathomechanisms using state-of-the-art biotechnology, but also construct gene-therapies directly translatable into clinical studies.
Affiliations
Publications generated during 1/2023-12/2025 with CMMC affiliation
2024 (up to June)
- Allroggen N, Breuer H, Bachmann S, Bell M, Zempel H. Studying Microtubule Dynamics in Human Neurons: Two-Dimensional Microtubule Tracing and Kymographs in iPSC- and SH-SY5Y-Derived Neurons for Tau Research. Methods Mol Biol. 2024;2754:561-580. doi: 10.1007/978-1-0716-3629-9_33. PMID: 38512690.
- Buchholz S, Bell-Simons M, Cakmak C, Klimek J, Gan L, Zempel H. Cultivation, Differentiation, and Lentiviral Transduction of Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Glutamatergic Neurons for Studying Human Tau. Methods Mol Biol. 2024;2754:533-549. doi: 10.1007/978-1-0716-3629-9_31. PMID: 38512688.
- Buchholz S, Bell-Simons M, Haag N, Zempel H. Tracking Tau in Neurons: How to Grow, Fix, and Stain Primary Neurons for the Investigation of Tau in All Developmental Stages. Methods Mol Biol. 2024;2754:507-519. doi: 10.1007/978-1-0716-3629-9_29. PMID: 38512686.
- Buchholz S, Bell-Simons M, Zempel H. Tracking Tau in Neurons: How to Transfect and Track Exogenous Tau in Primary Neurons. Methods Mol Biol. 2024;2754:499-506. doi: 10.1007/978-1-0716-3629-9_28. PMID: 38512685.
- Buchholz S, and Zempel H (2024). The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes. Alzheimers Dement. doi:10.1002/alz.13784.
- Buchholz S, and Zempel H (2024). Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons. Neural Regen Res19, 1655-1657. doi:10.4103/1673-5374.389644.
- Langerscheidt F, Bell-Simons M, Zempel H. Differentiating SH-SY5Y Cells into Polarized Human Neurons for Studying Endogenous and Exogenous Tau Trafficking: Four Protocols to Obtain Neurons with Noradrenergic, Dopaminergic, and Cholinergic Properties. Methods Mol Biol. 2024;2754:521-532. doi: 10.1007/978-1-0716-3629-9_30. PMID: 38512687.
- Langerscheidt F, Wied T, Al Kabbani MA, van Eimeren T, Wunderlich G, and Zempel H (2024). Genetic forms of tauopathies: inherited causes and implications of Alzheimer's disease-like TAU pathology in primary and secondary tauopathies. J Neurol. doi:10.1007/s00415-024-12314-3.
- Lilis P, Al Kabbani MA, Zempel H. Optimized Calcium-Phosphate-Based Co-transfection of Tau and tdTomato into Human iPSC-Derived Neurons for the Study of Intracellular Distribution of Wild-type and Mutant Human Tau. Methods Mol Biol. 2024;2754:551-560. doi: 10.1007/978-1-0716-3629-9_32. PMID: 38512689.
- Zempel H. Genetic and sporadic forms of tauopathies-TAU as a disease driver for the majority of patients but the minority of tauopathies. Cytoskeleton (Hoboken). 2024 Jan;81(1):66-70. doi: 10.1002/cm.21793. Epub 2023 Oct 5. PMID: 37795931.