Multi-omic signatures of ALS-spectrum disorders

/ABSTRACT Loss of upper motor neurons (UMNs) and lower motor neurons (LMNs) is characteristic for classic amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that generally results in death within two to five years after the onset of symptoms. The motor phenotypic spectrum of ALS ranges from primary lateral sclerosis (PLS) with pure UMN dysfunction to progressive muscular atrophy (PMA) with pure LMN dysfunction. It is important to distinguish patients with PLS and PMA, because they exhibit a slower disease progression, resulting in a longer survival after disease onset, than patients with classic ALS. Even though it has been shown that RNA-binding proteins and splicing events (e.g., cryptic exons) play a critical role in these diseases, little is known about contributing transcripts. Hence, we will set out to identify relevant transcripts and dysregulated pathways that may drive UMN versus LMN pathology. As such, we will acquire the transcriptome of patients belonging to the ALS spectrum (Aim 1), assessing the motor cortex from post-mortem specimens. Because we will use both bulk and single-nuclei approaches, employing long-read sequencing technologies, we can accurately quantify genes and individual transcripts, comprehensively interrogate cell-type-specific gene expression and splicing changes, and reveal vulnerable cell populations. Additionally, since most cases remain genetically unexplained, despite the fact that numerous genes have been implicated in ALS pathogenesis, we will complete thorough genomic studies (Aim 2). Because we postulate that genetic causes or risk factors may have stayed hidden due to sequencing technologies utilized, we are proposing to perform long-read whole-genome sequencing, which gives us the opportunity to deal with highly repetitive or complex regions, thereby assisting in unraveling the genetic architecture of ALS and its spectrum disorders. Taken together, our innovative multi-omic studies can potentially uncover genetic drivers that may determine the degree of UMN and LMN involvement, possibly nominating biomarker candidates and promising therapeutic targets for these debilitating diseases. Project Number: 1R01NS140081-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Marka Van Blitterswijk | Institution: MAYO CLINIC JACKSONVILLE, JACKSONVILLE, FL | Award Amount: $622,792 | Activity Code: R01 | Study Section: Genetics of Health and Disease Study Section[GHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11362882