Biology subjects

Popova, B.

Publications and source records attributed to Popova, B..

3 recordsLinked to original sources

bioRxiv2026

Blm10/PA200-activated 20S proteasomes promote α-synuclein degradation and bypass proteasome inhibition in Parkinson disease models

Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinsons disease (PD). PD is characterized by the aggregation of alpha-synuclein (Syn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of Syn into aggregates and their propagation disrupts key proteostasis pathways, including the ubiquitin-proteasome system (UPS) or autophagy, contributing to cellular dysfunction and neuronal death. This study identified the proteasome activator Blm10 and its human ortholog PA200 as modulators of Syn degradation and toxicity. The conserved Blm10/PA200 protein plays a key role in regulating proteasome activity and assembly. The Syn expression increases Blm10 protein stability through autophagy inhibition, in a manner dependent on Syn phosphorylation at S129 in yeast. Overexpression of BLM10 or PA200 reduces Syn aggregation and enhances Syn turnover via activation of the 20S proteasome in yeast and mammalian cells. Blm10 and PA200-capped 20S proteasomes efficiently degrade both monomeric as well as oligomeric Syn in vitro. Notably, capped proteasomes retain proteolytic activities in presence of Syn, indicating resistance to Syn-induced inhibition, in contrast to 20S or 26S proteasomes. These results reveal a distinct proteasome subtype that bypasses UPS impairment and restores proteolytic capacity under proteotoxic stress. Our findings establish Blm10/PA200 as critical regulator of Syn proteostasis and highlight its protective role in maintaining protein homeostasis and cell viability under conditions of Syn toxicity.

cell biology↗

bioRxiv2025

The homeobox transcription factor HbxB coordinates distinct gene regulatory networks for asexual development and secondary metabolism in Aspergillus nidulans

Formation of conidia as asexual spores and sometimes worldwide distribution through the air is a very important feature of the fungal life style. This process is controlled by several regulatory proteins, including homeobox domain transcription factors. HbxB is one such regulator with implications in the control of development, secondary metabolism and various stress responses in the filamentous fungus Aspergillus nidulans. However, the molecular mechanism of the regulatory role of HbxB during asexual development is still elusive. Here we show that HbxB is a nuclear localized protein with great impact on asexual sporogenesis. Employment of high throughput assays like chromatin immunoprecipitation (ChIP-seq) and transcriptomics (RNA-seq), elucidated the in vivo binding landscape of HbxB in a genome-wide scale. A set of 238 genes as direct targets of HbxB were identified. A nine bases DNA motif where HbxB prefers to bind in vivo was discovered as HbxB response element (HRE). HbxB is influencing the expression of genes encoding master regulators of the asexual development such as SclB, PpoC, FlbA and FlbC. Moreover, the direct transcriptional control of the secondary metabolites sterigmatocystin and emericellamides biosynthesis by HbxB was discovered. Lastly also a previously elusive mutual regulatory control circuit between HbxB and two major regulators of the asexual development SclB and MsnA was found. Both of these regulators can directly induce the expression of hbxB. This study provides a detailed molecular mechanism on how HbxB controls A. nidulans asexual sporulation. ImportanceFungal distribution mainly relies on the formation of spores that are subsequently dispersed in different media to ensure colonization of substrates and the survival of the fungus. The asexual developmental program is a widely used strategy in the fungal kingdom for production of spores (conidia). The HbxB transcription factor is a nuclear localized, homeobox domain protein, with a strong impact on asexual sporulation of presumably numerous fungal species. This study enhances our understanding of the mechanism with which HbxB exerts its regulatory actions. HbxB is binding in vivo to specific DNA regulatory elements of genes encoding proteins with key roles in asexual development (like SclB, MsnA and PpoC), secondary metabolism (such as genes from the sterigmatocystin and emericellamide clusters) and stress response/tolerance. Overall, these findings open a window into how Hbx regulators orchestrate and coordinate fungal asexual developmental programs genome-wide at the molecular level.

molecular biology↗

bioRxiv2025

Gradient of Wnt signaling facilitates Mef2 heterogeneity and limits commitment of the developmental muscle progenitor pool

During skeletal muscle development, the timing and extent of lineage commitment towards differentiation must be coordinated to ensure proper tissue formation while preserving undifferentiated progenitors for adult stem cell function. This balance requires spatial and temporal regulation of cell fate and transcriptional regulators to act as key mediators of lineage progression. The transcription factor Mef2 is a key activator of myogenic differentiation across vertebrates and invertebrates. However, the mechanisms that spatially restrict Mef2 expression within the developing niche to limit muscle progenitor (MP) commitment towards differentiation remains less well characterized. Using the developmental flight muscle progenitor niche in Drosophila, a system that parallels vertebrate myogenesis, we investigated the transcriptional and spatial regulation of MP fate at a developmental timepoint when Mef2 expression begins to rise but precedes overt differentiation. We identified a spatially distinct subpopulation of MPs with low Mef2 expression and elevated Wnt/{beta}-catenin signaling. Within the broader MP pool, graded Wnt activity emerged as a key source of Mef2 heterogeneity: high Wnt activity led to strong repression of Mef2 via Armadillo/{beta}-catenin and TCF-dependent regulation. Moderate Wnt activity, meanwhile, not only repressed Mef2 expression but also sustained expression of zfh1, a conserved transcription factor linked to MP maintenance and adult muscle stem cell identity. Contrary to its well-established role in promoting myogenesis, Wnt/{beta}-catenin signaling in this early spatial context instead promotes a less committed state, leading to a subset of MPs with particular low Mef2 level. These findings highlight greater spatial complexity within the developing muscle progenitor niche than previously recognized, with potential implications for conserved strategies of muscle stem cell regulation across species.

developmental biology↗