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This is in part due to the deceptive simplicity of the question and our limited understanding of how protein homeostasis is maintained in the compartmentalized cells of the central nervous system, especially in the context of the adult brain. Building on studies from simple cell\u2010based systems and invertebrate animals, we recently identified a protein central to the specific and selective turnover of aggregated proteins in the adult brain, the autophagy\u2010linked FYVE protein (Alfy)\/Wdfy3. Depletion of Alfy levels in a mouse model of Huntington's disease showed that it accelerated the accumulation of the aggregated mutant huntingtin protein, as well as the onset of behavioral deficits. Although the motor dysfunction was accelerated in the model, this was in the absence of increasing overt cell loss, implicating protein aggregates as a modifier of circuit dysfunction rather than driving degeneration per se. We discuss these findings in the context of what is known about protein accumulation and how we can use proteins such as Alfy to determine if protein accumulation is a shared pathogenic event across different adult\u2010onset diseases. \u00a9 2021 International Parkinson and Movement Disorder Society<\/jats:p>","DOI":"10.1002\/mds.28522","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T08:47:52Z","timestamp":1616489272000},"page":"1061-1069","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Dissolving the Complex Role Aggregation Plays in Neurodegenerative Disease"],"prefix":"10.1002","volume":"36","author":[{"given":"Katherine R.","family":"Croce","sequence":"first","affiliation":[{"name":"Doctoral Program in Pathobiology Columbia University  New York New York 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