Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

Darwich, Nabil F.; Phan, Jessica M.; Kim, Boram; Suh, EunRan; Papatriantafyllou, John; Changolkar, Lakshmi; Nguyen, Aivi T.; O’Rourke, Caroline M.; He, Zhuohao; Porta, Sílvia; Gibbons, Garrett S.; Luk, Kelvin C.; Papageorgiou, Sokratis G.; Grossman, Murray; Massimo, Lauren; Irwin, David J.; McMillan, Corey T.; Nasrallah, Ilya M.; Toro, Camilo; Aguirre, Geoffrey K.; Deerlin, Vivianna M. Van; Lee, Edward B.

doi:10.1126/science.aay8826

Cited by 105 publications

(147 citation statements)

References 35 publications

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“…p97 plays a central role in many cellular processes, including endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation, chromatin-associated degradation, autophagy, and endosomal trafficking 5 . Mutations in human p97 have been found in multisystem proteinopathy (MSP), a dominantly inherited degenerative disorder that can affect muscle, bone and the central nervous system, that can manifest clinically as inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS) 6, 7 . Moreover, recent studies have also targeted p97 for the treatment of cancer and viral infections 8, 9 .…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insight into substrate processing and allosteric inhibition of human p97

Pan

et al. 2021

Preprint

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p97, also known as valosin-containing protein (VCP), processes ubiquitinated substrates and plays a central role in cellular protein homeostasis. Mutations in human p97 are associated with multisystem proteinopathy (MSP), a dominantly inherited degenerative disorder that can affect muscle, bone and the central nervous system. It is also a drug target for cancer therapy with various inhibitors developed over the past decade. Despite significant structural insights into the fungal homologue of p97, Cdc48, little is known about how human p97 processes its substrates and how the activity is allosterically affected by inhibitors. Here, we report a series of cryo-electron microscopy (cryo-EM) structures of substrate-engaged human p97 complex with resolutions ranging from 2.9 to 3.8 Angstrom that captured power stroke-like motions of both the D1 and D2 ATPase rings of p97. The structures elucidated how the unfolded substrate is engaged in the pore at atomic level. Critical conformational changes of the inter-subunit signaling (ISS) motifs were revealed, providing molecular insights into substrate translocation. Furthermore, we also determined cryo-EM structures of human p97 in complex with NMS-873, the most potent p97 inhibitor, at a resolution of 2.4 Angstrom. The structures showed that NMS-873 binds at a cryptic groove in the D2 domain and interacts with the ISS motif, preventing its conformational change, thus blocking substrate translocation allosterically. Finally, using NMS-873 at a substoichiometric concentration, we captured a series of intermediate states, suggesting how the cofactor Npl4 coordinates with the D1 ring of p97 to initiate the translocation.

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Section: Introductionmentioning

confidence: 99%

Mechanistic insight into substrate processing and allosteric inhibition of human p97

Pan

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…p97 plays a central role in many cellular processes, including endoplasmic reticulum-associated degradation, mitochondrial-associated degradation, chromatin-associated degradation, autophagy and endosomal trafficking 5 . Mutations in human p97 have been found in multisystem proteinopathy (MSP), a dominantly inherited degenerative disorder that can affect muscle, bone and the central nervous system, and which can manifest clinically as inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS) 6,7 . Moreover, recent studies have also targeted p97 for the treatment of cancer and viral infections 8,9 .…”

mentioning

confidence: 99%

Mechanistic insight into substrate processing and allosteric inhibition of human p97

Pan

et al. 2021

Nat Struct Mol Biol

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“…While PSP is typically sporadic, this kindred provided a unique opportunity to compare the neuropathology of two affected siblings who were differentially exposed to Gosuranemab. Neither sibling had mutations in microtubule-associated protein tau (MAPT) or valosin-containing protein (VCP) which are the only known genes linked to autosomal dominant forms of primary tauopathy [11].…”

Section: Resultsmentioning

confidence: 99%

Tau immunotherapy is associated with glial responses in FTLD-tau

et al. 2021

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Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.

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Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

Cited by 105 publications

References 35 publications

Mechanistic insight into substrate processing and allosteric inhibition of human p97

Mechanistic insight into substrate processing and allosteric inhibition of human p97

Mechanistic insight into substrate processing and allosteric inhibition of human p97

Tau immunotherapy is associated with glial responses in FTLD-tau

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