In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Guo, Qiang; Lehmer, Carina; Martínez-Sánchez, Antonio; Rudack, Till; Beck, Florian; Hartmann, Hannelore; Pérez‐Berlanga, Manuela; Frottin, Frédéric; Hipp, Mark S.; Hartl, F. Ulrich; Edbauer, Dieter; Baumeister, Wolfgang; Fernández-Busnadiego, Rubén

doi:10.1016/j.cell.2017.12.030

Cited by 351 publications

(354 citation statements)

References 96 publications

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“…This observation could also be explained by the presence of active proteasomes within the phagosomal/endolysosomal lumen. Recent cryo-electron microscopy analysis has shown that proteasomes localize to the cytosol and cytosolic protein aggregates in neuronal cells (Asano et al, 2015;Guo et al, 2018). TAP-Like (TAP-L), a TAP homologue localized to lysosomal membranes, has been suggested as a candidate, although it was recently shown that BMDC derived from TAP-L knockout mice do not exhibit impaired cross-presentation (Lawand et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of proteasome substrates identified have been cytosolic, nuclear, or membrane proteins. Recent cryo-electron microscopy analysis has shown that proteasomes localize to the cytosol and cytosolic protein aggregates in neuronal cells (Asano et al, 2015;Guo et al, 2018). However, studies in yeast and plant cells have shown that endocytic compartments contain proteasomes, although no evidence was presented that they were active (Marshall et al, 2015;Cohen-Kaplan et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

et al. 2019

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During MHC‐I‐restricted antigen processing, peptides generated by cytosolic proteasomes are translocated by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, where they bind to newly synthesized MHC‐I molecules. Dendritic cells and other cell types can also generate MHC‐I complexes with peptides derived from internalized proteins, a process called cross‐presentation. Here, we show that active proteasomes within cross‐presenting cell phagosomes can generate these peptides. Active proteasomes are detectable within endocytic compartments in mouse bone marrow‐derived dendritic cells. In TAP‐deficient mouse dendritic cells, cross‐presentation is enhanced by the introduction of human β2‐microglobulin, which increases surface expression of MHC‐I and suggests a role for recycling MHC‐I molecules. In addition, surface MHC‐I can be reduced by proteasome inhibition and stabilized by MHC‐I‐restricted peptides. This is consistent with constitutive proteasome‐dependent but TAP‐independent peptide loading in the endocytic pathway. Rab‐GTPase mutants that restrain phagosome maturation increase proteasome recruitment and enhance TAP‐independent cross‐presentation. Thus, phagosomal/endosomal binding of peptides locally generated by proteasomes allows cross‐presentation to generate MHC‐I‐peptide complexes identical to those produced by conventional antigen processing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

et al. 2019

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“…For example, poly-GA is highly aggregation-prone, presumably due to its hydrophobic nature. Electron microscopy studies of cerebellar granule cells from a C9orf72 -FTD/ALS patient showed that poly-GA NCIs contain 15–17 nm filamentous structures [174], but a more recent study using cryo-electron tomography showed that poly-GA aggregates in cultured neurons are made up of densely packed twisted 13–15 nm thick ribbons with varying length and width [52]. Further understanding of the ultrastructural featuresof DPR aggregates could shed light on toxicity mechanisms and guide therapeutic development.…”

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

et al. 2018

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What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

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“…Primary hippocampal cultures were prepared from E19 rats as described previously and plated on glass coverslips coated with ª 2018 The Authors EMBO Molecular Medicine 10: e8558 | 2018 poly-D-lysine (Guo et al, 2018). Lentivirus was packaged in HEK293FT cells as described (Guo et al, 2018).…”

Section: Neuronal Cell Culture and Lentivirus Productionmentioning

confidence: 99%

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

et al. 2018

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CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29‐year‐old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled‐coil‐helix‐coiled‐coil‐helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild‐type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N‐terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide‐bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.

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In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Cited by 351 publications

References 96 publications

Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

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