Biology subjects

Di Gregorio, S. E.

Publications and source records attributed to Di Gregorio, S. E..

4 recordsLinked to original sources

bioRxiv2026

Differently sized soluble α-synuclein species from multiple system atrophy and Lewy body disease brains display different seeding propensities

Different conformations, or strains, of -synuclein (-syn) aggregates are believed to be responsible for the distinct seeding propensities, propagation profiles, and clinical presentations in Lewy body diseases (LBD) and multiple system atrophy (MSA). While biochemical properties and strain differences of insoluble deposits have been extensively characterized, the understanding of what influence soluble -syn species may have on these processes is limited to a small number of studies focusing on complex mixtures of soluble species or on a single - synucleinopathy. Given that soluble oligomers are considered highly pathologically relevant, we isolated and characterized the biochemical, seeding, and toxicity properties of size-fractionated soluble -syn species from MSA and LBD brains, comparing them to species from control brains without known neurological disease (Ctrl). We observed that levels of differently sized oligomers phosphorylated at Ser129, as well as soluble large oligomers (>450 kDa), were increased in LBD compared to both MSA and Ctrl brains. Nevertheless, species derived from MSA brain exhibited seeding activity across the spectrum of -syn species (oligomers, monomers, and truncated forms) in the seed amplification assay, whereas only oligomeric species (>150 kDa) from LBD cases were seeding-prone. In the HEK293 -syn (A53T)-YFP biosensor line, as well as in murine primary neurons, only large oligomers (>450 kDa) from MSA cases induced seeding and aggregation of -syn. Taken together, our study suggests that soluble -syn species derived from MSA and LBD brains show different biochemical, aggregation and seeding patterns, presumably due to strain variations of the respective oligomers. Our findings provide novel insight into the pathogenesis of different -synucleinopathies, which may guide us in the development of targeted therapeutics.

neuroscience↗

bioRxiv2024

TUDCA modulates drug bioavailability to regulate resistance to acute ER stress in Saccharomyces cerevisiae

Cells counter accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) through activation of the Unfolded Protein Response (UPR). Small molecules termed chemical chaperones can promote protein folding to alleviate ER stress. The bile acid tauroursodeoxycholic acid (TUDCA), has been described as a chemical chaperone. While promising in models of protein folding diseases, TUDCAs mechanism of action remains unclear. Here, we found TUDCA can rescue growth of yeast treated with the ER stressor tunicamycin (Tm), even in the absence of a functional UPR. In contrast, TUDCA failed to rescue growth on other ER stressors. Nor could TUDCA attenuate chronic UPR associated with specific gene deletions or over-expression of a misfolded mutant secretory protein. Neither pretreatment with or delayed addition of TUDCA conferred protection against Tm. Importantly, attenuation of Tm-induced toxicity required TUDCAs critical micelle forming concentration, suggesting a mechanism where TUDCA directly sequesters drugs. Indeed, in several assays, TUDCA treated cells closely resembled cells treated with lower doses of Tm. In addition, we found TUDCA can inhibit dyes from labeling intracellular compartments. Thus, our study challenges the model of TUDCA as a chemical chaperone and suggests that TUDCA decreases drug bioavailability, allowing cells to adapt to ER stress.

cell biology↗

bioRxiv2021

A yeast model of the ALS protein Matrin3 uncovers Hsp90 and its co-chaperone Sti1 as modifiers of misfolding and toxicity

The MATR3 gene encoding the protein Matrin3 is implicated in the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Matrin3 forms neuronal cytoplasmic and nuclear inclusions in ALS-affected neurons. Additionally, 13 heterozygous missense mutations in MATR3 are identified in ALS patients. To further explore Matrin3 misfolding and toxicity, we established and characterized a yeast model. We demonstrate that wild type Matrin3 and the ALS-associated variant F115C are toxic and form inclusions in yeast. Our further characterization uncovers substantial modification of Matrin3 toxicity and inclusion formation by Hsp90 and its co-chaperones, specifically Sti1. Thus, our study demonstrates how specific branches of cellular protein quality control regulate the misfolding and toxicity of Matrin3. Summary StatementWe established and characterized a yeast model expressing human Matrin3, a protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Using this yeast model and mammalian neuronal cells, we showed that Matrin3 mislocalizes and forms inclusions, is cytotoxic, and increases sensitivity to cellular stress. We also uncovered that Hsp90 and particularly its co-chaperone Sti1 alter Matrin3 toxicity.

molecular biology↗

bioRxiv2020

Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

Protein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperones have a strong capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity. We further show that the co-chaperone Sti1 specifically interacts with and modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and its cellular toxicity.

cell biology↗