The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS). Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. But, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin-proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.

Microfluidic sorting offers a unique ability to isolate large numbers of cells for bulk proteomic or metabolomics studies but is currently limited by low throughput and persistent clogging at low flow rates. Recently we uncovered the physical principles governing the inertial focusing of particles in high-Reynolds numbers. Here, we superimpose high Reynolds inertial focusing on Dean vortices, to rapidly isolate large quantities of young and adult yeast from mixed populations at a rate of 107 cells/min/channel. Using a new algorithm to rapidly quantify budding scars in isolated yeast populations and system-wide proteomic analysis, we demonstrate that protein quality control and expression of established yeast aging markers such as CalM, RPL5, and SAM1 may change after the very first replication events, rather than later in the aging process as previously thought. Our technique enables the large-scale isolation of microorganisms based on minute differences in size (±1.5 μm), a feat unmatched by other technologies.