Mechanisms of protective UFM1-dependent IRE1 signaling in tauopathies

SUMMARY Pathological aggregation of the protein tau is a hallmark of Alzheimer’s disease and several related dementias, collectively referred to as tauopathies. Familial tauopathies caused by coding mutations in tau and experimental model systems support a causal role for tau aggregation in these diseases. Based on these findings, tau-lowering therapies using anti-sense oligonucleotides or antibodies are currently in clinical trials. However, potential drawbacks of these approaches are that the therapeutic modalities are expensive and would therefore be challenging to deploy in the large population of AD and tauopathy patients. Furthermore, therapies lowering total tau levels have the caveat that we insufficiently understand the physiological roles of tau, and lowering total tau may have detrimental effects. Therefore, therapies selectively targeting pathological forms of tau using small- molecule drugs remain a significant unmet need. Endogenous protein homeostasis mechanisms that lower pathological tau species may represent an attractive therapeutic target in AD and tauopathies. In previous work, the lab of MPI Dr. Kampmann used a genome-wide CRISPRi screen in human neurons to systematically uncover such mechanisms. The UFMylation pathway was an important class of hits in this screen, where knockdown reduced tau oligomers. In follow-up studies, Kampmann and collaborator Dr. Li Gan confirmed that inhibition of the UFMylation pathway lowers pathological tau species in different human neuron and mouse models of tauopathy. However, the underlying molecular mechanisms that link UFMylation to tau proteostasis are unknown. MPI Dr. Kopito has previously elucidated the mechanisms and targets of the UFMylation pathway using biochemical and structural approaches. His work established that the 60S ribosomal subunit is the target of UFMylation and that this modification is essential to dislodge terminated ribosomes from SEC61 translocons in the endoplasmic reticulum (ER). In unpublished findings, his lab uncovered that failure of UFMylation to recycle ribosomal subunits specifically activates adaptive signaling through the ER proteostasis sensor IRE1 and activation of the transcription factor XBP1s to drive a transcriptional program of protective stress response effectors. We hypothesize that this response serves as a feedback loop to ensure levels of available SEC61 translocons, while also upregulating other protein homeostasis factors that facilitate clearance of pathological states of tau. The proposed research will (1) Define the molecular mechanism by which disruption of UFMylation and translocon homeostasis activates protective IRE1 signaling in the absence of unfolded proteins, (2) Elucidate the mechanism by which protective IRE1 signaling suppresses tau aggregation, and (3) Validate the mechanism and therapeutic potential of IRE1 activation in tauopathy mouse models. Project Number: 1R01AG096698-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Martin Kampmann (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $681,908 | Activity Code: R01 | Study Section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND] View on NIH RePORTER: https://reporter.nih.gov/project-details/11236473