Biology subjects

Jonson, M.

Publications and source records attributed to Jonson, M..

4 recordsLinked to original sources

bioRxiv2025

Alternative splicing generates a Ribosomal Protein S24 isoform induced by neuroinflammation and neurodegeneration

Neuroinflammation, particularly that involving reactive microglia, the brains resident immune cells, is implicated in the pathogenesis of major neurodegenerative diseases. However, early markers of this process are in high demand. Multiple studies have reported changes in ribosomal protein (RP) expression during neurodegeneration, but the significance of these changes remains unclear. Ribosomes are evolutionarily conserved protein synthesizing machines, and although commonly viewed as invariant, accumulating evidence suggest functional ribosome specialization through variation in their protein composition. By analyzing cell type-specific translating mRNAs from mouse brains, we identify distinct RP expression patterns between neurons, astrocytes, and microglia, including neuron-specific RPs, Rpl13a and Rps10. We also observed complex expression relationships between RP paralogs and their canonical counterparts, suggesting regulated mechanisms for generating heterogeneous ribosomes. Analysis across brain regions revealed that Rplp0 and Rpl13a, commonly used normalization references, show heterogeneous expression, raising important methodological considerations for gene expression studies. Importantly, we show that Rps24, an essential ribosome component that undergoes alternative splicing to produce protein variants with different C-termini, exhibits striking cell type-specific isoform expression in brain. The Rps24c isoform is predominantly expressed in microglia and is increased by neuroinflammation caused by aging, neurodegeneration, or inflammatory chemicals. We verify increased expression of S24-PKE, the protein variant encoded by Rps24c, in brains with Alzheimers disease, Parkinsons disease, and Huntingtons disease, and relevant mouse models, using isoform-specific antibodies. These findings establish heterogeneous RP expression as a feature of brain cell types and identify Rps24c/S24-PKE as a novel marker for neuroinflammation and neurodegeneration.

neuroscience↗

bioRxiv2022

Cerebellar granule neurons induce Cyclin D1 in an early stage of Huntington's disease

Although Huntingtons disease (HD) is predominantly defined by selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm, 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting predominantly of granule cells, a cell type commonly considered disease-resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected. Furthermore, increased expression of cyclin D1 (Ccnd1) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulators Cbx2, Cbx4 and Cbx8 point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.

bioinformatics↗

bioRxiv2021

Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific brain regions and cell types. This selectivity may arise from cells possessing varying capacities to regain proteostasis when stressed by cytotoxic protein conformers. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite having a normal outward appearance. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated a sharply reduced synthesis of ribosomal and mitochondrial components, 2) excitatory neurons showed increased expression of cytoskeletal genes, and 3) inhibitory neurons revealed reduced expression of circadian rhythm network genes. Further assessment for the role of circadian rhythms using a jet lag paradigm modestly exacerbated disease. These data demonstrate that early translatome responses to neurodegeneration emerge prior to other signs of disease and are unique to different cell types. Therapeutic strategies may need to target multiple pathways, each in specific populations of cells, early in the disease process.

neuroscience↗

bioRxiv2020

Insights into calcium signaling and gene expression in astrocytes uncovered with 129S4 Slc1a3-2A-CreERT2 knock-in mice

AO_SCPLOWBSTRACTC_SCPLOWGenetic variation is a primary determinant of phenotypic diversity within populations. In laboratory mice, genetic variation has often been regarded as a serious experimental confounder, and thus minimized through inbreeding. However, generalizations of results obtained with inbred strains need to be made with caution. Effects of genetic background on traits need to be controlled, especially when working with complex phenotypes and disease models. Here we compared behavioral parameters of C57Bl/6 - the mouse strain most widely used for biomedical research - with those of 129S4. Our data demonstrate high within-strain and intra-litter behavioral hyperactivity in C57Bl/6. In contrast, 129S4 had relatively consistent activity levels throughout life. This consistency would be advantageous for studying neurodegeneration and aging, when mice need to be analyzed for long periods. However, the majority of mouse models and transgenic tools are on a C57Bl/6 background. We recently established six popular Cre driver lines and two Cre effector lines in 129S4. To augment this collection, we genetically engineered a Cre mouse line to study astrocytes directly in 129S4, which we describe here. For functional validation, it was crossed with two Cre effector lines, each in a different genomic locus, and showed in both cases that it was functional and astrocyte-specific. Calcium currents studied with gCaMP5g-tdTomato were more heterogenous, lasted longer and had a higher amplitude in cortical compared to hippocampal astrocytes. Translatomes studied with RiboTag revealed that some genes thought to mark neurons are also expressed in astrocytes, that genes linked to a single neurodegenerative disease have highly divergent expression patterns, and that ribosome proteins are non-uniformly expressed across brain regions and cell types.

neuroscience↗