bims-lypmec 2024-09-08 papers

Cell Mol Biol Lett. 2024 Sep 05. 29(1): 116

Lysosome quality control in health and neurodegenerative diseases.

Veronica Ferrari, Barbara Tedesco, Marta Cozzi, Marta Chierichetti, Elena Casarotto, Paola Pramaggiore, Laura Cornaggia, Ali Mohamed, Guglielmo Patelli, Margherita Piccolella, Riccardo Cristofani, Valeria Crippa, Mariarita Galbiati, Angelo Poletti, Paola Rusmini.

Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.

Keywords: Galectins; Lysosomal membrane permeabilization; Lysosome; Lysosome quality control; Neurodegeneration

DOI: https://doi.org/10.1186/s11658-024-00633-2

Nat Commun. 2024 Sep 05. 15(1): 7743

The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation.

Agata N Makar, Alina Boraman, Peter Mosen, Joanne E Simpson, Jair Marques, Tim Michelberger, Stuart Aitken, Ann P Wheeler, Dominic Winter, Alex von Kriegsheim, Noor Gammoh.

Autophagy is a finely orchestrated process required for the lysosomal degradation of cytosolic components. The final degradation step is essential for clearing autophagic cargo and recycling macromolecules. Using a CRISPR/Cas9-based screen, we identify RNAseK, a highly conserved transmembrane protein, as a regulator of autophagosome degradation. Analyses of RNAseK knockout cells reveal that, while autophagosome maturation is intact, cargo degradation is severely disrupted. Importantly, lysosomal protease activity and acidification remain intact in the absence of RNAseK suggesting a specificity to autolysosome degradation. Analyses of lysosome fractions show reduced levels of a subset of hydrolases in the absence of RNAseK. Of these, the knockdown of PLD3 leads to a defect in autophagosome clearance. Furthermore, the lysosomal fraction of RNAseK-depleted cells exhibits an accumulation of the ESCRT-III complex component, VPS4a, which is required for the lysosomal targeting of PLD3. Altogether, here we identify a lysosomal hydrolase delivery pathway required for efficient autolysosome degradation.

DOI: https://doi.org/10.1038/s41467-024-52049-3

Cell Mol Life Sci. 2024 Sep 03. 81(1): 382

Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.

Lijun Dai, Miao Liu, Wei Ke, Liam Chen, Xin Fang, Zhentao Zhang.

In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.

Keywords: Biomarkers; Chaperone-mediated autophagy; GBA1; TMEM175; Therapeutic strategies

DOI: https://doi.org/10.1007/s00018-024-05419-5