Biology subjects

Baginska, M.

Publications and source records attributed to Baginska, M..

3 recordsLinked to original sources

bioRxiv2025

ER stress and cell fate: FKBP2 regulates proinsulin folding and α- vs. β-cell differentiation via NFAT and HDAC9

The continuous demand for insulin production places a burden on the endoplasmic reticulum (ER) of pancreatic {beta} cells, making them highly susceptible to protein misfolding and ER stress. While general ER chaperones are known to be essential for {beta} cell homeostasis, the specific mechanisms by which individual chaperones facilitate proinsulin folding and influence cell fate remain unclear. This study identifies FK506-binding protein 2 (FKBP2), an ER-localized cis-trans prolyl isomerase, as a critical regulator of human {beta} cell differentiation and proinsulin processing. Using loss- and gain-of-function FKBP2 models in human pluripotent stem cells (hPSCs), we demonstrate that its deficiency impairs insulin processing, leading to abnormal insulin granule morphology and reduced insulin secretion. Unexpectedly, our findings reveal a crucial and unreported role for FKBP2 in cell fate determination. Single-cell RNA sequencing reveals that FKBP2 loss disrupts the proper endocrine lineage allocation, causing a shift towards the cell formation at the expense of {beta} cells. In KO endocrine cells, we observed sustained ER stress and elevated intracellular calcium levels, along with activation of the NFAT2-HDAC9 axis. Pharmacological inhibition of HDAC class IIa activity partially rescued {beta} cell differentiation, supporting a causal role for this pathway. Collectively, our results provide new mechanistic insights into how ER chaperones can control pancreatic development and contribute to the pathogenesis of diabetes.

cell biology↗

bioRxiv2025

L-DOPA induces spatially discrete changes in gene expression in the forebrain of mice with a progressive loss of dopaminergic neurons

L-3,4-Dihydroxyphenylalanine (L-DOPA) is effective at alleviating motor impairments in Parkinsons disease (PD) patients but has mixed effects on nonmotor symptoms and causes adverse effects after prolonged treatment. Here, we analyzed the spatial profile of L-DOPA-induced gene expression in the forebrain of mice with an inducible progressive loss of dopaminergic neurons (the TIF-IADATCreERT2 strain), with a focus on the similarities and differences in areas relevant to different PD symptoms. The animals received a 14-day L-DOPA treatment, and 1 h after the final drug injection, a spatial transcriptome analysis was performed on coronal forebrain sections. A total of 121 genes were identified as being regulated by L-DOPA. We found that the treatment had widespread effects extending beyond the primary areas involved in dopamine-dependent movement control. An unsupervised clustering analysis of the transcripts recapitulated the forebrain anatomy and indicated both ubiquitous and region-specific effects on transcription. The changes were most pronounced in layers 2/3 and 5 of the dorsal cortex and the dorsal striatum, where a robust increase in the abundance of activity-regulated transcripts, including Fos, Egr1, and Junb, was observed. Conversely, transcripts with a decreased abundance, e.g., Plekhm2 or Pgs1, were identified primarily in the piriform cortex, the adjacent endopiriform nucleus, and the claustrum. Taken together, our spatial analysis of L-DOPA-induced alterations in gene expression reveals the anatomical complexity of treatment effects, identifying novel genes affected by the drug, as well as molecular activation in brain areas relevant to the nonmotor symptoms of PD.

neuroscience↗

bioRxiv2023

Nonmotor symptoms associated with progressive loss of dopaminergic neurons in a mouse model of Parkinson's disease

Parkinsons disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse nonmotor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the nonmotor symptoms of PD in a mouse model of the disease (the TIF-IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the step cadence and sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent nonmotor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

neuroscience↗