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Liquid-liquid phase separation (LLPS) is emerging as a major principle for the mesoscale organization of proteins, RNAs, and membrane-bound organelles into biomolecular condensates. These condensates allow for rapid cellular responses to changes in metabolic activities and signaling. Nowhere is this regulation more important than in neurons and glia, where cellular physiology occurs simultaneously on a range of time- and length-scales. In a number of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), misregulation of biomolecular condensates leads to the formation of insoluble aggregates—a pathological hallmark of both sporadic and familial ALS. Here, we summarize how the emerging knowledge about the LLPS of ALS-related proteins corroborates with their aggregation. Understanding the mechanisms that lead to protein aggregation in ALS and how cells respond to these aggregates promises to open new directions for drug development.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the death of upper and lower motor neurons. While most cases of ALS are sporadic, some of the familial forms of the disease are caused by mutations in the gene encoding for the RNA-binding protein FUS. Under physiological conditions, FUS readily phase separates into liquid-like droplets in vivo and in vitro. ALS-associated mutations interfere with this process and often result in solid-like aggregates rather than fluid condensates. Yet, whether cells recognize and triage aberrant condensates remains poorly understood, posing a major barrier to the development of novel ALS treatments. Using a combination of ALS-associated FUS mutations, optogenetic manipulation of FUS condensation, chemically induced stress, and pH-sensitive reporters of organelle acidity, we systematically characterized the cause-effect relationship between the material state of FUS condensates and the sequestering of lysosomes. From our data, we can derive three conclusions. First, regardless of whether we use wild-type or mutant FUS, expression levels (i.e., high concentrations) play a dominant role in determining the fraction of cells having soluble or aggregated FUS. Second, chemically induced FUS aggregates recruit LAMP1-positive structures. Third, mature, acidic lysosomes accumulate only at FUS aggregates but not at liquid-condensates. Together, our data suggest that lysosome-degradation machinery actively distinguishes between fluid and solid condensates. Unraveling these aberrant interactions and testing strategies to manipulate the autophagosome-lysosome axis provides valuable clues for disease intervention.