Return fellowship

• Applicant: Dr. Isabell Cordts, from 4/2024 until 9/2024
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542485510

The motor phenotypic spectrum of amyotrophic lateral sclerosis (ALS) varies from pure upper motor neuron (UMN) to pure lower motor neuron (LMN) involvement, epitomized by primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA), respectively. Furthermore, there is considerable clinical, genetic and pathological overlap between ALS and frontotemporal dementia (FTD), which are thought to belong to a disease spectrum. It is crucial to identify genetic factors responsible for the substantial phenotypic variability of ALS and its spectrum disorders in order to understand the biology of these diseases and to develop therapeutic strategies. The primary research objective of this project is to identify unique genetic lesions and transcript variants that might contribute to UMN and/or LMN pathology as well as the development of FTD (vs. classical ALS). To this end, we aim to perform different short- and long-read sequencing experiments on both affected brain regions and blood comparing patients with varying degrees of UMN and LMN as well as cognitive impairment. We propose to use a highly innovative long-read RNA sequencing technology (Iso-Seq) to capture the full-length transcriptome. First, we will assess the motor cortex of a unique cohort of patients who received a neuropathological diagnosis of PLS (n=20), classic ALS (n=20) and PMA (n=20). This enables us to uncover novel, aberrantly spliced and/or disease-specific transcripts. Importantly, these transcriptomic data will nicely complement our ongoing long-read RNA sequencing study for a clinical cohort of patients for whom blood is available. Second, to identify drivers of FTD in patients with ALS, we will leverage our existing short-read RNA-seq datasets for the frontal cortex and cerebellum. These short-read datasets will be complemented with Iso-Seq data for both regions. Aforementioned studies will reveal important candidates, which will be validated, replicated and further investigated in a large collection of clinical and pathological specimens, including biofluids and brain tissue. Ultimately, our experiments will result in the identification of novel disease modifiers, biomarkers and/or therapeutic targets. Of particular relevance to this project is that my mentor, Dr. Van Blitterswijk, has extensive experience performing genetic/genomic/transcriptomic studies. In fact, her laboratory already did large-scale short-read RNA sequencing studies and she is currently leading multiple long-read RNA and DNA sequencing studies in brain and blood. Thus, the proposed project nicely complements these datasets and can take advantage of optimized methods and analysis pipelines.

• DFG Programme: WBP Return Grant
• Host: Professor Dr. Bernhard Hemmer