Biology subjects

Auld, D.

Publications and source records attributed to Auld, D..

5 recordsLinked to original sources

bioRxiv2026

CSF complement proteins are associated with early tau pathology and synaptic damage in an asymptomatic population at risk of Alzheimer's disease

Complement-mediated neuroinflammation has been implicated in Alzheimer's disease (AD), but its role during the pre-symptomatic phase of the disease remains unclear. In the PREVENT-AD cohort of cognitively unimpaired individuals at increased familial risk of AD, we investigated whether CSF complement proteins relate to early AD pathology and synaptic dysfunction, then assessed our results' reproducibility across the clinical AD spectrum. Baseline CSF C1q, C3, C3b, and Factor H were measured in relation to CSF AD biomarkers, synaptic proteins, cognition, MRI volumetry, and amyloid and tau PET. Key findings were then examined in 708 participants from ADNI spanning cognitively normal, mild cognitive impairment (MCI), and dementia stages of AD. In PREVENT-AD, C1q was positively associated with CSF P-tau181, T-tau, and multiple synaptic markers including ADAM23, GAP43, SNAP25, and SYT1. Factor H showed similarly strong positive associations with P-tau181, T-tau, ADAM22, ADAM23, GAP43, and SYT1. By contrast, C3 showed minimal associations, while C3b displayed weaker positive relationships with P-tau181, T-tau, ADAM22, and ADAM23. Complement proteins were not robustly associated with amyloid or tau PET, and only C1q related to lower global cognitive performance. In ADNI, C1q emerged as the most consistent analyte, showing positive associations with tau, neurofilament light, and synaptic markers across all diagnostic groups. C3 exhibited predominantly negative associations, whereas C3b and Factor H showed stage-dependent relationships, particularly with evident neurodegeneration and synaptic injury in symptomatic individuals. These findings identify complement dysregulation, especially involving C1q, as an early correlate of tau-linked synaptic pathology, and support a role for complement activation in the AD molecular cascade.

neuroscience↗

bioRxiv2026

Scalable platform for cellular and biochemical screening of combinatorial small-molecule libraries in droplets

A new pattern of hit discovery is emerging with the rise of chemocentric modalities, such as chemical induced proximity (CIP). Synthesis and functional screening of dynamic, purpose-built libraries, such as E3 ligase biased libraries for targeted protein degradation (TPD), is redefining the druggable landscape. However, this new paradigm arguably lies beyond the remit of conventional screening methods which have been optimized for static, diversity-oriented libraries. To address this gap, we developed microfluidic compound screening in droplets (MicDrop), a scalable platform where purpose-built DNA-encoded one-bead one-compound library members are individually tested at high concentrations in pico-liter sized droplets for either biochemical or cellular function. A proof-of-concept CRBN library demonstrated the robustness of the workflow through an IKZF3 degradation screen which discovered an unexpected succinimide-based IKZF3 degrader, while reproducing the relative potency ranking of reference compounds. Screening of a prospective VHL library for CDO1 recruitment and degradation demonstrated that orthogonal assays gave an informative consensus hit list and an actionable machine-learning (ML) recruitment model. These findings establish a blueprint for intentional discovery of chemical inducers of proximity, while producing reliable data to accelerate ML-based design-make-test-analyze (DMTA) cycles in pursuit of new therapeutics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/730915v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@12de3cborg.highwire.dtl.DTLVardef@1c6618dorg.highwire.dtl.DTLVardef@12ea42eorg.highwire.dtl.DTLVardef@11cea77_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cell Biology↗

bioRxiv2026

Phenotypic screening for small molecules that lower PrP in cultured cells

PrP lowering is a validated therapeutic hypothesis in prion disease. To identify small molecules that reduce PrP levels, we performed phenotypic screening in cultured cells. To prioritize PrP specificity in our primary screen, we generated mouse N2a cells stably expressing GFP and used high content imaging analysis to select compounds that lowered PrP without affecting GFP signal or cell viability. Screening a curated library of 3,492 compounds with annotated mechanisms of action identified two small molecules, EYH (PubChem CID: 71678945) and LCZ (PubChem CID: 24970350), that selectively and dose-dependently lowered PrP. Proteomics on whole cell lysates identified PrP as the #1 or #2 most potently downregulated out of 8,722 proteins detected. Both compounds minimally affected Prnp mRNA, reduced expression of exogenously transfected PrP, and remained potent in non-dividing primary cells, consistent with a post-translational mechanism. Co-treatment with the proteasome inhibitor MG132 yielded accumulation of unglycosylated PrP, demonstrating proteasome clearance of PrP. However, both compounds showed limited or no activity in human cell lines, and failed to reduce PrP in vivo after 14 days of treatment. These findings highlight the challenges associated with mechanism-agnostic phenotypic screening for PrP-lowering compounds and support prioritizing compounds with known mechanisms of action.

neuroscience↗

bioRxiv2024

PTPRS is a novel marker for early tau pathology and synaptic integrity in Alzheimer's disease

We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimers disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimers disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early tau pathology and synaptic degeneration in Alzheimers disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower P-tau181 and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimers disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.

neuroscience↗

bioRxiv2023

SALL4B, not targeted by IMiD, is important for SALL4-mediated tumorigenesis

Immunomodulatory (IMiD) drugs have shown a prominent therapeutic activity in hematologic malignancies; however, their usage in solid tumors is limited. The oncofetal protein SALL4 is essential for cancer cell survival. While IMiDs can induce SALL4 degradation, they fail to induce cell death in SALL4-expressing cancer cell lines. Here, we observed that this inefficacy arose from their selective degradation of the long SALL4 isoform, while sparing the short SALL4B isoform. Selective silencing of SALL4B phenocopied total SALL4 depletion by inducing cancer apoptosis, underscoring the critical role of SALL4B in cancer maintenance. Recognizing that IMiDs cant degrade SALL4B, we performed a high-throughput screen to identify compound(s) that could achieve this. We identified a small molecule compound that degrades both SALL4 isoforms with enhanced potency towards SALL4B in a cereblon- and proteasome-dependent manner. This compound suppressed cancer cell proliferation and attenuated tumor development in both cell line and patient-derived xenograft models. Transcriptomic analyses further revealed convergent effects of genetic and pharmacologic SALL4B depletion on DNA damage response and replication pathways. Together, these findings identify SALL4B as the therapeutically relevant isoform in SALL4-dependent cancers and establish isoform-aware targeted degradation as a strategy to overcome the limitation of IMiDs in solid tumors. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/548071v2_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@99670dorg.highwire.dtl.DTLVardef@13ca58forg.highwire.dtl.DTLVardef@998e7eorg.highwire.dtl.DTLVardef@15a1875_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract | Identification of QE: a non-IMiDs degrader capable of degrading both SALL4A and SALL4B, triggers anti-cancer effects beyond IMiDs, and Impacts of QE on Key Validated SALL4B Targets and Pathways C_FIG

cancer biology↗