The ubiquitin-proteasome system, essential for essential for degrading unwanted or misfolded proteins (Schmidt et al. 2021), was impaired with age, leading to the accumulation of neurotoxic aggregates such as β-amyloid, tau, and α-synuclein, which are associated with neurodegenerative diseases such as AD, PD, Huntington's disease, and amyotrophic lateral sclerosis (supplementary fig. Here, MAPT is linked to amyotrophic lateral sclerosis.