TABLE.

Summary of Proteostasis Factors Valosin-Containing Protein (VCP), 26S Proteasome, Hsp104, and C9orf72 Role in Proteostasis, Their Substrates, and Mutation-Associated Diseases (PDB: 6OA9, 6MSD, 5VJH, 6LT0; EMDB: 7479)

Proteostasis Factor	Role in Proteostasis	Associated Substrates	Mutation-Associated Diseases
Valosin-containing protein	Remove proteins from complexes, membranes, and aggregates May directly precede the 26S proteasome	Tau, transactive response DNA-binding protein 43 kDa (TDP-43)	Vacuolar tauopathy, multisystem proteinopathy
26S proteasome	Final factor in that degrades polypeptides in the ubiquitin proteasome system	Amyloid precursor protein, Tau, α-synuclein, polyQ aggregates, poly-GA aggregates	N/A
Hsp104	Native yeast protein that has shown promise as effective disaggregase	Seminal amyloid, TDP-43, α-synuclein, FUS, stress granules	N/A (yeast protein)
C9orf72	Regulates autophagy potentially through endosomal regulation May indirectly affect many parts of proteostasis	Rab8a, Rab11a, Arf1, Arf5, Arf6, 26S proteasome (binding partner with 65 other neurodegenerative associated proteins)	Amyotrophic lateral sclerosis, frontotemporal degeneration