The twilight of the aggresome: from self-exile to the rise of new defensive compartments
Speaker: Dr Zhaoyu Li
Queensland Brain Institute
University of Queensland
The twilight of the aggresome: from self-exile to the rise of new defensive compartments
Abstract: Neurons are constantly challenged by proteotoxic stress during aging, a key driver of neurodegenerative diseases. Aggresomes are well-recognized quality-control compartments that sequester misfolded proteins and facilitate their clearance. However, we found that aggresomes themselves undergo functional decline and become damaged under sustained proteotoxic conditions. As long-lived cells, how neurons adapt to the deterioration of this primary defense system remains poorly understood. Using C. elegans models expressing neurodegenerative disease–associated misfolded proteins and tracking individual neurons across the lifespan, we observed that large, damaged aggresomes are not efficiently degraded intracellularly. Instead, they are expelled from the soma through a previously uncharacterized process, in which the aggresome is extruded via a filopodium-like structure. Strikingly, dysfunction of aggresomes also triggers the emergence of another type of quality-control compartment, which we term SolAS (Soluble misfold protein-triggered Axonal Swellings). These structures sequester soluble misfolded proteins into neurites, redistributing proteotoxic burden away from the soma, and facilitate their clearance via exophers and microvesicles. Together, extrusion of damaged aggresomes and the formation of SolAS act cooperatively to remodel proteostasis capacity and maintain cellular integrity, ensuring continued protection of neurons as primary quality-control systems decline with age.
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Neuroscience seminars at the QBI play a major role in the advancement of neuroscience in the Asia-Pacific region. The primary goal of these seminars is to promote excellence in neuroscience through the exchange of ideas, establishing new collaborations and augmenting partnerships already in place.
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