Abstract: Misfolding of proteins as well as their aggregation is a major driver of age-related neurodegenerative diseases. Hence, cells have evolved sophisticated protein quality control mechanisms. Mainly the ubiquitin-proteasome-system (UPS) and the autophagosome-lysosome-system, specifically a macroautophagy pathway called “aggrephagy”, govern the disposal of aggregates. However, the cell still has to cope with fundamental challenges to keep the consequences of, e.g., age-related insufficient clearance low. The clearance of dysfunctional or misfolded proteins that can lead to toxic aggregates depends on sensing and sequestration mechanisms, which usually include molecular chaperones (e.g., heat shock protein 70 [HSP70] proteins) and co-chaperones (e.g., BAG proteins). Accordingly, the overburdening of UPS capacity or its age-related decline represents a fundamental challenge for postmitotic cells such as neurons in particular. Among other influences and effects, one hallmark of proteinopathies that is associated with neurodegeneration is precisely this overload of the UPS and the resulting accumulation of aggregation-prone proteins, such as the microtubule-associated protein tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, or superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis. In case of a serious impairment or overload of the UPS, protein aggregates translocate to a larger, clearly defined structure called “aggresome”. This term was coined by the Kopito lab more than two decades ago (Johnston et al., 1998). The aggresome itself is assumed to be a protective cellular response that condenses potentially cytotoxic aggregates and also serves as a transit center for autophagic clearance. This perinuclear accumulation of aggregated proteins at the microtubule organizing center is clearly characterized by its vimentin cage. Accordingly, the formation of this up to several µm large structure requires a fundamental rearrangement of the intermediate vimentin cytoskeleton and represents a final condensation stage. Thus, pre-aggresomal structures emerge during its genesis. However, in spinal cord motor neurons from SOD1G85R transgenic mice, for instance, those aggresomes occur after the onset of disease symptoms.