Science on Target: Q2 2026 Research Spotlight
July 8, 2026 Amy Easton
Basic Biology Consortium breaks new ground in ALS
In 2022, Target ALS awarded funding to Drs. Jonathan Cooper-Knock (University of Sheffield, project lead) and Michael Snyder (Stanford University), along with fellow consortium members Drs. Ophir Shalem (University of Pennsylvania) and Eran Hornstein (Weizmann Institute), for their project “Exploring the landscape of ALS genetics with machine learning and optical pooled screens.” The consortium aimed to identify cell-specific genomic functions and genetic drivers of disease by using high-throughput profiling and machine learning to map cellular phenotypes of ALS risk and severity genes. Prior to the start of the project, Drs. Cooper-Knock and Snyder established a strong foundation by identifying new candidate ALS-associated genes using their machine-learning platform, RefMap.
During this project, Dr. Snyder’s laboratory performed integrated single-cell RNA-sequencing and single-cell chromatin accessibility (ATAC-seq) profiling to create a “multiome” atlas of the ALS motor cortex. The multiome dataset constructed by Dr. Snyder became the largest of its kind produced for any neurodegenerative disease and included tissue from c9orf72-ALS patients and sporadic ALS (sALS) patients, and non-neurological controls. A key advantage of the multiome dataset was that it provided the consortium the ability to determine changes in the entire gene-regulatory network, including gene expression and open chromatin instead of active enhancers that are dependent on TDP-43 mislocalization. Dr. Cooper-Knock’s laboratory analyzed the multiome to identify cell-specific risk genes by performing a trajectory analysis and then constructing gene-regulatory networks. The multiome dataset has started to uncover novel cell-specific therapeutic targets with the potential to yield many more.
High-throughput profiling of 200 candidate genes put forth by Drs. Snyder and Cooper-Knock were evaluated in Dr. Shalem’s laboratory. They evaluated the impact of candidate gene knockdown on TDP-43 mislocalization and stress granule recruitment and assembly using newly developed methods for optical pooled screening.
Finally, Dr. Hornstein developed a new computer vision / machine-learning model from neuro-cell biology, called ‘NOVA’ (Neuronal Organellomics Vision Atlas) to quantify high-resolution images of membrane-bound and biomolecular condensates and integrate these readouts with TDP-43 mislocalization and other disease-relevant phenotypic endpoints. The result is a high-throughput, multiparametric deep organellar phenotyping platform capable of detecting organelle crosstalk dysfunction as a novel class of disease-relevant phenotype, one that would be undetectable by conventional single-endpoint screens and directly linking upstream genetic drivers to downstream cellular pathology.
WDR49+ Astrocytes Mediate TDP-43 Aggregate Propagation
Early results from Cooper-Knock’s trajectory analysis pointed towards ALS-specific astrocytes as a cell-type of interest, in particular, ALS-associated astrocytes expressing WDR49. While WDR49-positive astrocytes have been previously associated with frontotemporal dementia (FTD) and TDP-43 pathology, their relationship with ALS was largely unclear. In their BioRxiv preprint, “Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes,” Cooper-Knock et al. identified WDR49+ astrocytes, through the development of an integrated single-nucleus multiomic analysis of ALS motor cortex, as a potential neuroprotective response to prevent the propagation of extracellular TDP-43 aggregates in c9orf72-ALS and sporadic ALS (sALS).
Key findings:
- ALS-associated chromatin changes were identified across multiple cell types, but astrocytes showed the most significant transcriptomic alterations, marked by stress response and inflammatory signatures
- WDR49+ astrocytes are associated with a neuroprotective response to TDP-43 pathology. If WDR49+ astrocytes fail to contain TDP-43 pathology, for example because of loss-of-function mutations within WDR49, then this is sufficient to cause ALS.
- Consistent with a neuroprotective role, WDR49 expression in spinal cord tissue of ALS patients is positively correlated with patient survival, making this an attractive therapeutic target.
- WDR49 co-localizes with promyelocytic leukemia (PML) nuclear bodies, a membraneless organelle in the nucleus that regulates transcript expression and responds to DNA damage, in a SUMOylation-dependent manner.
- WDR49 expression is a determinant of astrocyte reactivity, including production and release of extracellular vesicles (EVs) biogenesis
Proposed model: WDR49+ astrocytes normally suppress prion-like TDP-43 aggregate spread by mounting a compensatory secretory response to extracellular protein aggregates, and that loss of this capacity lowers the threshold for ALS pathogenesis.
Caveats: The causal relationship between WDR49+ astrocytes and extracellular TDP-43 requires further validation, and the reasons these astrocytes become dysfunctional in sporadic ALS remain unknown.
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