Biology subjects

Sandhu, D.

Publications and source records attributed to Sandhu, D..

5 recordsLinked to original sources

bioRxiv2026

Polyglutamine aggregation proceeds by stochastic nucleation in the C. elegans nervous system

Fibrillar protein aggregation is the hallmark of a wide variety of neurodegenerative diseases. It is still poorly understood how soluble proteins transition to fibrillar aggregates, in particular within the complex environment of cells and tissues. Here, we employ the nematode Caenorhabditis elegans to elucidate the molecular mechanisms of polyglutamine aggregation in the nervous system of a multicellular animal. By using fluorescence microscopy in combination with mathematical modelling, we find that polyglutamine aggregation occurs by stochastic nucleation in individual neurons, at a rate that is of the same order of magnitude as previously determined for muscle cells. The J-protein DNAJB6 strongly suppresses polyglutamine aggregation in both tissues, consistent with a mechanism in which aggregation is limited by primary nucleation. We confirm that the same mechanism holds true for a construct including the disease-relevant flanking regions of Huntingtin exon 1. Altogether, our data reveal that polyglutamine aggregation occurs spontaneously and largely independent of the cellular context.

biophysics↗

bioRxiv2025

Untargeted metabolomics reveals key metabolites and genes underlying salinity tolerance mechanisms in maize

Understanding the physiological, metabolic, and genetic mechanisms underlying salt tolerance is essential for improving crop resilience and productivity, yet their complex interactions remain poorly defined. We compared physiological and metabolic responses to salinity between two contrasting maize inbred lines: the salt-sensitive C68 and the salt-tolerant NC326. The senstitivity of C68 was characterized by reduced shoot and root dry weights and plant height, high tissue accumulation of Na and Cl, but low K, and lower leaf proline accumulation compared to the salt-tolerant NC326. Untargeted metabolomics identified 56 metabolites categorized as constitutively upregulated or salt-responsive. In NC326, constitutive accumulation of flavonoids, including schaftoside, tricin, and kaempferol-related compounds in leaves suggests adaptive priming against oxidative stress, while constitutively higher lipids and fatty acids in roots may enhance membrane stability. Salt-responsive metabolites, notably antioxidants and lanosterol, highlighted inducible oxidative-stress mitigation and membrane-stabilization strategies. By integrating metabolomic and genetic analyses, we identified 10 candidate genes involved in the biosynthesis of key metabolites. These findings establish a comprehensive platform for functional validation of metabolites and candidate genes for developing maize varieties with improved resilience to soil salinity through targeted breeding or biotechnological strategies. Plane Language SummarySalinity, or high salt content in soil, is a major challenge to crop growth worldwide, reducing food production. Maize, an important crop globally, struggles to grow under salty conditions. This study compared two maize types--one that grows well in salty soil and one that struggles--to understand how maize plants adapt to salt stress. Using advanced techniques, we measured hundreds of compounds (metabolites) in plant tissues to identify protective substances. We discovered that plants resistant to salt stress naturally produce higher amounts of protective substances, helping them avoid damage from salt. Additionally, we found specific metabolites that plants produce when exposed to salty conditions to protect their cells. We also identified genes that control the production of these important metabolites. This research provides new insights into how maize plants manage salt stress and highlights potential targets for developing crops that grow better in saline soils. Core IdeasO_LIMaize genotypes differ in growth, ion balance, and proline under salt stress. C_LIO_LIMetabolomics reveals pre-stress buildup of protective flavonoids and fatty acids. C_LIO_LISalt triggers metabolic changes like sterol increase to protect membranes. C_LIO_LIGenetic analysis links genes to key metabolites controlling salt tolerance. C_LIO_LIMetabolite-gene insights guide breeding of maize for salt resilience C_LI

plant biology↗

bioRxiv2022

Plant phase extraction (PPE): A novel method for enhanced discovery of RNA-binding proteome in plants

RNA-binding proteins (RBPs) are versatile effectors in posttranscriptional gene regulation. Systematic profiling of RBPs in plants has been limited to proteins interacting with polyadenylated (poly(A)) RNAs due to the lack of an efficient method of isolating RBPs associated with non-poly(A) RNAs. Here we reported the establishment and application of plant phase extraction (PPE) as a novel method to comprehensively discover the RNA-binding proteome in Arabidopsis leaf tissues, leading to the isolation of 1,169 RBPs, of which 673 corroborate with previously reported RBPs and 496 are novel RBPs. PPE showed unmatched ability in capturing 374 diverse RNA-binding domains (RBDs), while 44% of the RBPs lack recognized RBDs. PPE recovered far more ribosomal and tRNA-related RBPs and metabolic enzymes with moonlighting RBP functions than any other individual report from plants, signifying its advantage in unbiasedly retrieving non-poly(A) and unconventional RBPs. We proposed that intrinsically disordered regions (IDRs) contributed to the non-classical binding of some novel RBPs, and provided the first evidence that enzymatic domains from metabolic enzymes have additional roles in RNA-binding. Taken together, our findings demonstrated that PPE is an effective approach to identifying a wide range of RBPs in complex plant tissues and may have broad biological implications.

molecular biology↗

bioRxiv2019

Accelerated trans-sulfuration metabolically defines a discrete subclass of ALS patients

Amyotrophic lateral sclerosis (ALS) is a disease characterized by progressive paralysis and death. Most ALS cases are sporadic (sALS) and patient heterogeneity poses a formidable challenge for the development of viable biomarkers and effective therapies. Applying untargeted metabolite profiling on 77 sALS patient-derived primary dermal fibroblast lines and 45 sex/age matched controls, we found that [~]25% of cell lines (termed sALS-1) are characterized by upregulated trans-sulfuration, where methionine-derived homocysteine is channeled into cysteine and glutathione synthesis. sALS-1 fibroblasts exhibit a growth defect when grown under oxidative conditions, that can be fully-rescued by N-acetylcysteine. [U-13C]-glucose tracing shows that activation of the trans-sulfuration pathway is associated with accelerated glucose flux into the TCA cycle. Based on four metabolites, we developed a support vector machine model capable of distinguishing sALS-1 with 97.5% accuracy. Importantly, plasma metabolite profiling identifies a systemic perturbation of cysteine metabolism as a hallmark of sALS-1. These results indicate that sALS patients can be stratified into distinct metabotypes, differently sensitive to metabolic stress, and provides new insights into metabolic biomarkers for personalized sALS therapy.

neuroscience↗

bioRxiv2018

Identification of a Distinct Metabolomic Subtype of Sporadic ALS Patients

Sporadic amyotrophic lateral sclerosis (sALS) is a progressive motor neuron disease resulting in paralysis and death. Genes responsible for familial ALS have been identified, however the molecular basis for sALS is unknown. To discover metabotypic biomarkers that inform on disease etiology, untargeted metabolite profiling was performed on 77 patient-derived dermal fibroblast lines and 45 age/sex-matched controls. Surprisingly, 25% of sALS lines showed upregulated methionine-derived homocysteine, channeled to cysteine and glutathione (GSH). Stable isotope tracing of [U-13C]-glucose showed activation of the trans-sulfuration pathway, associated with accelerated glucose flux into the TCA cycle, glutamate, GSH, alanine, aspartate, acylcarnitines and nucleotide phosphates. A four-molecule support vector machine model distinguished the sALS subtype from controls with 97.5% accuracy. Plasma metabolite profiling identified increased taurine as a hallmark metabolite for this sALS subset, suggesting systemic perturbation of cysteine metabolism. Furthermore, integrated multiomics (mRNAs/microRNAs/metabolites) identified the super-trans-sulfuration pathway as a top hit for the sALS subtype. We conclude that sALS can be stratified into distinct metabotypes, providing for future development of personalized therapies that offer new hope to sufferers.

neuroscience↗