Biology subjects

Bonoldi, E.

Publications and source records attributed to Bonoldi, E..

2 recordsLinked to original sources

bioRxiv2025

PARylation in Parkinson's disease: a bridge between Lewy body formation and neuronal cell death

Poly-ADP-ribosylation (PARylation), catalyzed by the enzyme PARP1, involves the addition of poly-ADP-ribose polymers (PAR) and has been associated with -synuclein aggregation in Parkinsons disease (PD) models. This study aimed to unravel the role of PARylation in -synuclein aggregation and neuronal cell death in the complex environment of post-mortem human PD brains. Using high-resolution imaging and 3D reconstruction analysis, we observed that PAR accumulate in the cytoplasm in regions affected by PD pathology, preceding the formation of -synuclein oligomers. Additionally, we found that PAR and stress granules contribute to the formation of Lewy bodies. Increased colocalization of PAR with mitochondria in the substantia nigra of PD patients, along with the presence of PAR-positive condensed DNA, further suggests a role in neuronal cell death. Collectively, our findings reveal a critical involvement of PARylation in the pathological mechanisms underlying neurodegeneration in PD and position PARylation as a potential therapeutic target. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/642849v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@64858aorg.highwire.dtl.DTLVardef@17b4706org.highwire.dtl.DTLVardef@73f865org.highwire.dtl.DTLVardef@1b8d619_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Amyloid aggregates accumulate in melanoma metastasis driving YAP mediated tumor progression

Melanoma progression is generally associated to increased Yes-associated protein (YAP) mediated transcription. Actually, mechanical signals from the extracellular matrix are sensed by YAP, which activates proliferative genes expression, promoting melanoma progression and drug resistance. Which and how extracellular signals induce mechanotransduction is not completely understood. Herein, by secretome studies, we revealed an extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), together with proteins that assist amyloids maturation into fibrils. Indeed, we confirmed the presence of amyloid-like aggregates similar to those detected in Alzheimer disease. These aggregates were enriched in metastatic cell lines as well as in human melanoma biopsies, compared to their primitive counterpart. Mechanistically, we proved that beta-secretase (BACE) regulates the maturation of these aggregates and that its inhibition hampers YAP activity. Moreover, recombinant PMEL fibrils induce per se mechanotransduction promoting YAP activation. Finally, BACE inhibition affects cell proliferation and increases drug sensitivity. These results highlight the importance of amyloids for melanoma survival and the potential of beta-secretase inhibitors as new therapeutic approach to metastatic melanoma.

cancer biology↗