Biology subjects

Collins, M. A.

Publications and source records attributed to Collins, M. A..

6 recordsLinked to original sources

bioRxiv2025

Ubiquitin-Proteasome System Dysregulation in Alzheimer's Disease Impacts Protein Abundance

Alzheimers disease (AD) is a relentlessly progressive, fatal neurodegenerative disorder that results in widespread protein dysfunctions. However, the full extent of aberrant proteomic changes in AD and their impact remains unknown, in part, because of the challenges of comprehensively measuring the proteome. Here, we used plexDIA, an approach that provides deep proteomic coverage and high throughput by parallelizing the acquisition of peptides and samples, to characterize proteomic changes in AD. Using human dorsolateral prefrontal cortex tissue, we identified 281 differentially abundant proteins in AD. By systematically analyzing compartment and protein complex-specific shifts in protein abundance, we identified an AD-specific decrease in levels of the 20S proteasome, the catalytic core of the cells primary protein degradation pathway. This alteration was accompanied by widespread decreases in proteasome subunit stoichiometries. Many proteasome substrate proteins were negatively correlated with 20S levels and increased in AD, suggesting that reduced 20S levels leads to abnormal protein accumulation. By analyzing proteins increased in AD, we identify key properties of such proteins: They have fast degradation rates, they contain signal sequences that allow them to be targeted for proteasomal degradation, and they are targeted by quality control pathways that recognize mislocalized proteins. Changes in these gene products at the protein and mRNA levels were highly discordant, providing additional evidence for increased protein abundance driven by impaired clearance. We also identified coherent sets of ubiquitin system enzymes, proteins that target substrates for proteasomal degradation, whose levels robustly discriminate AD from non-AD samples. One subset exhibited consistent increases in AD, while another, which contained the tau E3 ligase Cul5, exhibited consistent decreases, revealing complex changes in the ubiquitin system in AD. Taken together, our results suggest that decreased ubiquitin-proteasome system capacity and impaired clearance of short-lived and mislocalized proteins contribute substantially to proteopathic burden in AD.

neuroscience↗

bioRxiv2024

Genotype-by-environment interactions shape ubiquitin-proteasome system activity

In genotype-by-environment interactions (GxE), the effect of a genetic variant on a trait depends on the environment. GxE influences numerous organismal traits across eukaryotic life. However, we have a limited understanding of how GxE shapes the molecular processes that give rise to organismal traits. Here, we characterized how GxE shapes protein degradation, an essential molecular process that influences numerous aspects of cellular and organismal physiology. Using the yeast Saccharomyces cerevisiae, we characterized GxE in the activity of the ubiquitin-proteasome system (UPS), the primary protein degradation system in eukaryotes. By mapping genetic influences on the degradation of six substrates that engage multiple distinct UPS pathways across eight diverse environments, we discovered extensive GxE in the genetics of UPS activity. Hundreds of locus effects on UPS activity varied depending on the substrate, the environment, or both. Most of these cases corresponded to loci that were present in one environment but not another ("presence / absence" GxE), while a smaller number of loci had opposing effects in different environments ("sign change" GxE). The number of loci exhibiting GxE, their genomic location, and the type of GxE (presence / absence or sign change) varied across UPS substrates. Loci exhibiting GxE were clustered at genomic regions that contain core UPS genes and especially at regions containing variation that affects the expression of thousands of genes, suggesting indirect contributions to UPS activity. Our results reveal highly complex interactions at the level of substrates and environments in the genetics of protein degradation.

genetics↗

bioRxiv2021

Genetic Basis of Variation in Ubiquitin-Proteasome System Activity

Ubiquitin-proteasome system (UPS) protein degradation regulates protein abundance and eliminates mis-folded and damaged proteins from eukaryotic cells. Variation in UPS activity influences numerous cellular and organismal phenotypes. However, to what extent such variation results from individual genetic differences is almost entirely unknown. Here, we developed a statistically powerful mapping approach to characterize the genetic basis of variation in UPS activity. Using the yeast Saccharomyces cerevisiae, we systematically mapped genetic influences on the N-end rule, a UPS pathway that recognizes N-degrons, degradation-promoting signals in protein N-termini. We identified 149 genomic loci that influence UPS activity across the complete set of N-degrons. Resolving four loci to individual causal nucleotides identified regulatory and missense variants in ubiquitin system genes whose products process (NTA1), recognize (UBR1 and DOA10), and ubiquitinate (UBC6) cellular proteins. Each of these genes contained multiple causal variants and several individual variants had substrate-specific effects on UPS activity. A cis-acting promoter variant that modulates UPS activity by altering UBR1 expression also alters the abundance of 36 proteins without affecting levels of the corresponding mRNAs. Our results demonstrate that natural genetic variation shapes the full sequence of molecular events in protein ubiquitination and implicate genetic influences on the UPS as a prominent source of post-translational variation in gene expression.

genetics↗

bioRxiv2020

The number of growing microtubules and nucleus-nucleus interactions uniquely regulate nuclear movement in Drosophila muscle

Nuclear movement is a fundamental process of eukaryotic cell biology. Skeletal muscle presents an intriguing model to study nuclear movement because its development requires the precise positioning of multiple nuclei within a single cytoplasm. Furthermore, there is a high correlation between aberrant nuclear positioning and poor muscle function. Although many genes that regulate nuclear movement have been identified, the mechanisms by which these genes act is not known. Using Drosophila melanogaster muscle development as a model system, and a combination of live-embryo microscopy and laser ablation of nuclei, we have found that phenotypically similar mutants are based in different molecular disruptions. Specifically, ensconsin (Drosophila MAP7) regulates the number of growing microtubules that are used to move nuclei whereas bocksbeutel (Drosophila emerin) and klarsicht (Drosophila KASH-protein regulate interactions between nuclei.

developmental biology↗

bioRxiv2020

Convergent molecular, cellular, and neural signatures of major depressive disorder

Major depressive disorder emerges from the complex interactions of biological systems that span across genes and molecules through cells, circuits, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to the onset and maintenance of depression requires a multi-scale approach, encompassing measures of brain structure and function as well as genetic and cell-specific genomic data. Here, we examined anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Genome Superstruct Project, and ENIGMA (combined N[≥]23,723). Integrative analyses incorporated measures of cortical gene expression, post-mortem patient transcriptional data, depression GWAS, and single-cell transcription. Neuroimaging correlates of depression and negative affect were consistent across the three independent datasets. Linking ex-vivo gene downregulation with in-vivo neuroimaging, we found that genomic correlates of depression-linked neuroimaging phenotypes tracked gene downregulation in post-mortem cortical tissue samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data implicated somatostatin interneurons and astrocytes as consistent cell associates of depression, through both in-vivo imaging and ex-vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multi-scale approaches, the genomic correlates of depression-linked brain function and structure were enriched for known and novel disorder relevant molecular pathways. These findings bridge across levels to connect specific genes, cell classes, and biological pathways to in-vivo imaging correlates of depression. Key FindingsO_LIMajor depressive disorder and negative affect are associated with replicable profiles of cortical anatomy and function across independent population-level neuroimaging datasets (combined N[≥]23,723). C_LIO_LISomatostatin interneurons are consistent spatial transcriptional associates of in-vivo depression-linked imaging phenotypes. C_LIO_LIIntegrative single-cell gene expression analysis associate somatostatin interneurons and astrocytes with both in-vivo depression-linked imaging and ex-vivo gene downregulation in independent MDD cortical tissue samples. C_LIO_LITranscriptional correlates of in-vivo depression imaging phenotypes selectively capture gene downregulation in post-mortem tissue samples from patients with depression, but not other psychiatric disorders. C_LIO_LIIndicating that some cell classes are preferentially sensitive to inherited disease liability, genome-wide risk for depression is enriched among interneurons, but not glia. C_LIO_LIGene associates of depression-linked anatomy and function identify specific neurotransmitter systems, molecular signaling pathways, and receptors, suggesting possible targets for pharmaceutical intervention. C_LI

neuroscience↗

bioRxiv2018

The transcriptional landscape of cortical interneurons underlies in-vivo brain function and schizophrenia risk

Inhibitory interneurons orchestrate information flow across cortex and are implicated in psychiatric illness. Although classes of interneurons have unique functional properties and spatial distributions throughout the brain, the relative influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped organizational properties of somatostatin and parvalbumin related transcripts within human and non-human primates. Interneuron spatial distributions recapitulate cortico-striato-thalamic functional networks and track regional differences in functional MRI signal amplitude. In the general population (n=9,627), parvalbumin-linked genes account for an enriched proportion of genome-wide heritable variance in in-vivo functional MRI signal amplitude. This relationship is spatially dependent, following the topographic organization of parvalbumin expression in independent post-mortem brain tissue. Finally, genetic risk for schizophrenia is enriched among interneuron-linked genes and predictive of cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular genetic basis of resting-state brain function across cortex is shaped by the spatial distribution of interneuron-related transcripts and underlies individual differences in risk for schizophrenia.\n\nKey FindingsO_LISpatial distributions of somatostatin (SST) and parvalbumin (PVALB) are negatively correlated in mature human and non-human primate cortex, paralleling patterns observed in utero.\nC_LIO_LISST and PVALB are differentially expressed within distinct limbic and somato/motor cortico-striato-thalamic networks, respectively.\nC_LIO_LIIn-vivo resting-state signal amplitude is heritable in the general population and tracks relative SST/PVALB expression across cortex.\nC_LIO_LISingle-nucleotide polymorphisms tied to PVALB-related genes account for an enriched proportion of the heritable variance in resting-state signal amplitude.\nC_LIO_LIPVALB-mediated heritability of resting-state signal amplitude in the general population is spatially heterogeneous, mirroring the cortical expression of PVALB in independent post-mortem brain tissue.\nC_LIO_LIPolygenic risk for schizophrenia is enriched among interneuron-linked genes and predicts resting-state signal amplitude in a manner that also follows the cortical expression of PVALB.\nC_LI

neuroscience↗