Originally discovered as regulators of cargo sorting during endosomal trafficking, ESCRT (endosomal sorting complexes required for transport) proteins are emerging as flexible machines that shape the behaviour of membranes throughout the cell. Deregulation of ESCRT activity is observed in neuro-degenerative diseases, virus infection and cancer. However, the mechanisms of pathogenesis involving ESCRTs have not yet fully come into focus. Here, we review the current knowledge of ESCRT function in health and disease and provide educated guesses for future research and focused therapeutic intervention.

Non-canonical Notch signaling encompasses a wide range of cellular processes, diverging considerably from the established paradigm. It can dispense of ligand, proteolytic or nuclear activity. Non-canonical Notch signaling events have been studied mostly in the fruit fly Drosophila melanogaster, the organism in which Notch was identified first and a powerful model for understanding signaling outcomes. However, non-canonical events are ill-defined and their involvement in human physiology is not clear, hampering our understanding of diseases arising from Notch signaling alterations. At a time in which therapies based on specific targeting of Notch signaling are still an unfulfilled promise, detailed understanding of non-canonical Notch events might be key to devising more specific and less toxic pharmacologic options. Based on the blueprint of non-canonical signaling in Drosophila, here, we review and rationalize current evidence about non-canonical Notch signaling. Our effort might inform Notch biologists developing new research avenues and clinicians seeking future treatment of Notch-dependent diseases.

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and -independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to-motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly-GA cellular uptake and propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.

Cells rely on molecular motors moving along an ever-shifting network of polymers (microtubules) for the targeted delivery of cell organelles to biologically-relevant locations. We present a stochastic model for a molecular motor stepping along a bidirectional bundle of microtubules, as well as a tractable analytical model. Using these models, we investigate how the preferred stepping direction of the motor (parallel or antiparallel to the microtubule growth, corresponding to kinesin and dynein motor families) quantitatively and qualitatively affects the cargo delivery. We predict which motor type is responsible for which cargo type, given the experimental distribution of cargo in the cell, and report experimental findings which support this guideline for motor classification.

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