Aggregates of the protein tau in neurons are a hallmark of Alzheimer's disease and related dementias, and are thought to be a key driver of neurodegeneration. However, we do not know which molecular mechanisms promote tau aggregation in vulnerable neurons and protect neurons resistant to tau aggregation.
In a project led by Dr. Avi Samelson when he was a postdoc in the Kampmann lab, we conducted a genome-wide CRISPRi screen in human neurons to uncover cellular factors that either promote or inhibit the accumulation of tau oligomers (the earliest stage of aggregation). We uncovered many such factors, including the E3 ubiquitin ligase CUL5, which we showed to bind to tau via the SOCS4 substrate adaptor to target it for degradation by the proteasome. We also found that oxidative stress caused by defective mitochondria can trigger biochemical changes in tau that promote its aggregation.
See here for the publication:
Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, Parra Bravo C, Bose RS, Travaglini KJ, Lam VL, Goodness D, Ta T, Dixon G, Marzette E, Jin J, Tian R, Tse E, Abskharon R, Pan HS, Carroll EC, Lawrence RE, Gestwicki JE, Rexach JE, Eisenberg DS, Kanaan NM, Southworth DR, Gross JD, Gan L, Swaney DL, Kampmann M (2026)
CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.
Cell 189(5):1517-1534.e19.
Read the press release by UCSF, and commentaries in Alzforum and Nature Molecular and Structural Biology.