Dissolving the Complex Role Aggregation Plays in Neurodegenerative Disease

Prominent neuropathological hallmarks of many adult-onset neurodegenerative diseases include the deposition and accumulation of misfolded proteins or conformers; however, their role in pathogenesis has remained unclear. 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-based 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-linked 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-onset diseases. © 2021 International Parkinson and Movement Disorder Society.