Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions

Cell & Bioscience, Год журнала: 2024, Номер 14(1)

Опубликована: Май 17, 2024

Abstract Background Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter fact, MMA patients manifest impairment primary metabolic network with profound damages that involve several cell components, many which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine uncover new pathologic mechanisms connected MUT through combination multi-proteomics bioinformatics approaches. Results Our data show proteome dysregulations, revealing molecular actors involved in lysosome autophagy functioning. To elucidate effects defective on lysosomal regulation, we analyzed morphology functionality MMA-lysosomes showed deep alterations, thus corroborating omics data. Lysosomes cells present as enlarged vacuoles low degradative capabilities. Notwithstanding, treatment an anti-propionigenic drug capable totally rescuing functional activity MUT-deficient cells. These results indicate strict connection between lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA. Conclusions Defective homeostatic regulation functions demonstrated prove triggers such dysfunctions impacting autophagosome-lysosome fusion activity.

Язык: Английский

Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis

Molecular Therapy — Methods & Clinical Development, Год журнала: 2025, Номер 33(1), С. 101432 - 101432

Опубликована: Фев. 12, 2025

Neuronal accumulation of amyloid aggregates is a hallmark brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this has not been understood. We demonstrate that elevated cathepsin B (CTSB) levels and CTSB leakage to cytoplasm triggers amyloidogenesis two LSDs. were 3- 5-fold cortices mouse models MPS IIIC (Hgsnat-Geo Hgsnat P304L ) sialidosis (Neu1 ΔEx3 ), as well cortical samples I, IIIA, IIIC, IIID patients. was found pyramidal layer IV-V neurons containing thioflavin-S+, β-amyloid+ consistent with pro-senile phenotype. In contrast, CTSB-deficient (Hgsnat /Ctsb -/- mice Neu1 chronically treated irreversible brain-penetrable inhibitor E64 showed drastic reduction neuronal thioflavin-S+/APP+ deposits. Neurons E64-treated also reduced P62+, LC3+ puncta, GM2 ganglioside, misfolded subunit C mitochondrial ATP synthase, restored autophagy. treatment rescued hyperactivity anxiety mice, implying may become novel pharmacological target for III similar

Язык: Английский

Cross-Linking Mass Spectrometry to Capture Protein Network Dynamics of Cell Membranome

Methods in molecular biology, Год журнала: 2024, Номер unknown, С. 241 - 258

Опубликована: Дек. 23, 2024

Язык: Английский