Single Nucleus Transcriptomic Profiling in Postmortem Spinal Cord of ALS Patients
Abstract
The central nervous system (CNS) is a highly complex network of diverse and coordinating cells. Dysfunction in this highly coordinated network is at the root of motor-neuron loss in patients on the amyotrophic lateral sclerosis-frontotemporal dementia clinical spectrum (ALS-FTD). To understand the selective and age-related loss of motor neurons (MNs) in patients with ALS-FTD, we need a comprehensive understanding of the repertoire of cells in the CNS and their respective role in health and disease. We propose to build an atlas of various types of cells in the CNS and understand how they malfunction in disease. To accomplish this, we will use approaches that leverage and integrate multiple types of data from post-mortem samples donated by ALS-FTD patients. Here, we propose interrogating postmortem tissue from the Target ALS (TALS) Post Mortem Tissue Core using single nucleus RNA-seq (snRNA-seq). These studies will be in synergy with other efforts: Through separately funded efforts, we have generated whole-genome and bulk RNA-sequencing data on all samples in this core; through NIH-funded efforts, we are also generating spatially resolved gene expression data from these samples. The long-term impact of these studies will bring genomics closer to the clinic. Through these studies, our goal is to bridge ALS and FTD centers by applying exciting new genomics technologies to explore the molecular underpinnings of the commonalities and differences between clinical presentations in ALS and FTD. Direct comparisons between FTD patients with and without the motor symptoms of ALS are rare, and the molecular underpinnings of the clinical, genetic, and pathological diversity on the ALS-FTD spectrum remain unknown. To address this challenge, the Target ALS Post Mortem core has partnered with the New York Genome Center to combine clinical and pathological expertise to assemble a large, deeply phenotyped cohort of post-mortem tissue across the ALS-FTD spectrum, and apply state-of-the-art multiomics approaches to molecular profiling and integrated data analysis. Our goal is to elucidate mechanisms that underlie similarities and distinctions between regions of an individual brain and between patients with different clinical phenotypes. Through this program, members of this diverse team will interact synergistically to (a) identify sensitive and specific pathological correlates of distinct clinical symptoms, and (b) understand the relative contributions of cell type-specific pathologies to clinical phenotypes in the brain regions associated with ALS-FTD. Our combined approach will provide a unique platform for driving transformative discoveries of the molecular, cellular, and regional correlates of ALS-FTD pathology and associated clinical outcomes. These studies will enable integration of data across sc/snRNAseq, histopathology imaging, and spatially resolved multi-omics modalities, allowing their joint analysis and the derivation of regulatory relationships between them. Taken together, the proposed study will yield a dataset and technological tool kit of great utility to a broad life science audience.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210126
Entities
People
- Hemali Phatnani
Organizations
- New York Genome Center
- United States Army