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might might - cambridge rare disease summit 2015

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Matthew Might, Ph.D. Associate Professor University of Utah Visiting Assoc. Professor Harvard Medical School Treating the Rarest of Diseases What do you do when you’re one of a kind? President NGLY1.org

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Page 1: Might Might - Cambridge Rare Disease Summit 2015

Matthew Might, Ph.D. Associate Professor University of Utah

Visiting Assoc. Professor Harvard Medical School

Treating the Rarest of Diseases What do you do when you’re one of a kind?

President NGLY1.org

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a story

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Bertrand

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Bertrand Russell

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NGLY1

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an odyssey

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“undiagnosed island”

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David Goldstein Vandana ShashiKelly Schoch

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{NGLY1

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{NGLY1

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“first”

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“only”

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Hudson Freeze (Sanford-Burnham-Prebys)

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“You got it.”

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“not actionable”

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NGLY1

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Science becomes medicine.

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Science becomes action.

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We can’t do this alone.

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I wrote a blog post.

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1. Go viral

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2. Rank high

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3898

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Meetings

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Foundations

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Natural experiments

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CDG Natural History

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Biomarkers!

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Hypoglycosylation!

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Assays

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Source: Hudson Freeze

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Model organisms

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Enzyme replacement

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PEG polymer TAT peptide

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Crowd science

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Su Lab @ Scripps

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mark2cure.org

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Repurposing

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Tufts CSSD

£1,600,000,000

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£1,600,000,0007000 ×

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£12,000,000,000,000

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Repurposing is key

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patient drug

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Basic science

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Endo-β-N-acetylglucosaminidase forms N-GlcNAcprotein aggregates during ER-associated degradationin Ngly1-defective cellsChengcheng Huanga,b, Yoichiro Haradaa, Akira Hosomia, Yuki Masahara-Negishia, Junichi Seinoa, Haruhiko Fujihiraa,Yoko Funakoshia, Takehiro Suzukic, Naoshi Dohmaec, and Tadashi Suzukia,b,1

aGlycometabolome Team, Systems Glycobiology Research Group, RIKEN–Max Planck Joint Research Center for Systems Chemical Biology, RIKEN GlobalResearch Cluster, Wako, Saitama 351-0198, Japan; bGraduate School of Science and Engineering, Saitama University, Saitama, Saitama 338-8570, Japan;and cCollaboration Promotion Unit, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan

Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 30, 2014 (received for reviewAugust 1, 2014)

The cytoplasmic peptide:N-glycanase (PNGase; Ngly1 in mice) isa deglycosylating enzyme involved in the endoplasmic reticulum(ER)-associated degradation (ERAD) process. The precise role ofNgly1 in the ERAD process, however, remains unclear in mammals.The findings reported herein, using mouse embryonic fibroblast(MEF) cells, that the ablation of Ngly1 causes dysregulation of theERAD process. Interestingly, not only delayed degradation but alsothe deglycosylation of a misfolded glycoprotein was observed inNgly1−/− MEF cells. The unconventional deglycosylation reactionwas found to be catalyzed by the cytosolic endo-β-N-acetylgluco-saminidase (ENGase), generating aggregation-prone N-GlcNAc pro-teins. The ERAD dysregulation in cells lacking Ngly1 was restoredby the additional knockout of ENGase gene. Thus, our study under-scores the functional importance of Ngly1 in the ERAD process andprovides a potential mechanism underlying the phenotypic conse-quences of a newly emerging genetic disorder caused by mutationof the human NGLY1 gene.

PNGase (Ngly1) | ENGase | protein aggregates | glycoprotein | ERAD

Endoplasmic reticulum (ER)-associated degradation (ERAD)constitutes one of the quality control mechanisms for newly

synthesized proteins in the ER. The ERAD process involvesa series of events, including aberrant domain recognition, ubiq-uitination, translocation from the ER to the cytosol, and deg-radation by proteasomes. Numerous lines of evidence point tothe existence of an ERAD system dedicated to N-linked glyco-proteins; in this system, specific N-glycan structures dictate thefolding status of client glycoproteins (1, 2). Once glycoproteins inthe ER lumen are targeted for degradation, they are retro-translocated into the cytosol, where the 26S proteasome playsa central role in their degradation (3). During the degradationprocess, N-glycans are removed by the action of the cytoplasmicpeptide:N-glycanase (PNGase) (4–6).Activity of the cytoplasmic PNGase was first described in mam-

malian cells (7, 8), and the gene encoding cytoplasmic PNGase(PNG1 in yeast; Ngly1/NGLY1 in mice/human) is widely dis-tributed throughout eukaryotes (9). The functional importanceof cytoplasmic PNGase in the ERAD process is evident in yeast(10–13). On the other hand, the suppression of Ngly1 gene ex-pression by siRNA in mammalian cells resulted in a reduceddeglycosylation of T-cell receptor α subunit (TCRα) or MHC classI heavy chain, whereas no significant delay in their degradationwas observed (14, 15). Moreover, Z-VAD-fmk, a pan-caspase in-hibitor, was shown to inhibit cytoplasmic PNGase activity in vivo,but it did not impede the degradation of MHC class I heavy chain(16). Consequently, the functional importance of the cytoplasmicPNGase remains elusive in mammalian cells.PNGase-mediated deglycosylation generates free oligosaccharides

in the cytosol (17). Recent evidence suggests that a nonlysosomaldegradation pathway exists for these cytosolic free glycans (17).

This degradation process involves cytosolic endo-β-N-acetylglu-cosaminidase (ENGase) (18, 19). Although the ENGase is believedto be involved in the catabolism of cytosolic free oligosaccharides,recent evidence shows that it can deglycosylate glycoproteins in vivoto generate N-GlcNAc–bearing proteins in Arabidopsis thaliana(20), raising the possibility that this enzyme may also act as adeglycosylation enzyme for misfolded glycoproteins in the cytosol(21, 22) (Fig. 1A).Recently, patients harboring mutations on the NGLY1 gene, an

ortholog of the cytoplasmic PNGase in mammalian cells (23), havebeen described (24, 25). Although this observation emphasizes thefunctional importance of this protein in mammalian cells, mecha-nistic insight into the phenotypic consequences of these patientsremains unclarified. In this study, we established an ERAD modelsubstrate, RTAΔm, and demonstrated that the delay in its degra-dation was evident in Ngly1−/− mouse embryonic fibroblast (MEF)cells. Interestingly, the delay was canceled by additional geneknockout of ENGase. The degradation of RTAΔm in double-knockout cells remains proteasome-dependent, clearly indicatingthat the presence of an N-glycan on RTAΔm did not affect theefficiency of proteasomal degradation. Moreover, the occurrenceof N-GlcNAc–modified RTAΔm in Ngly1−/− MEF cells was iden-tified by MS analysis, demonstrating that the ENGase-mediated

Significance

In the endoplasmic reticulum (ER), N-glycans on glycoproteinsplay important roles in dictating the folding status of proteinsby a sophisticated N-glycan–dependent protein quality controlmachinery. In this study we identified the dysregulation of ER-associated degradation (ERAD) in cells that were defective inthe cytosolic deglycosylating enzyme, Ngly1. ERAD dysregula-tion was caused by an unexpected deglycosylating activity ofendo-β-N-acetylglucosaminidase, another cytosolic deglycosy-lation enzyme, and this action resulted in the intracellularformation of protein aggregates. Our results clearly point tothe critical role of N-glycans even in cytosolic events of theERAD process by controlling the conformation/solubility ofproteins. This study may also provide a potential mechanismfor explaining the pathology of a human genetic disordercaused by mutations in the NGLY1 gene.

Author contributions: C.H. and Tadashi Suzuki designed research; C.H., Y.H., A.H., Y.M.-N.,J.S., H.F., Y.F., Takehiro Suzuki, and N.D. performed research; Y.H., A.H., Y.M.-N., and Y.F.contributed new reagents/analytic tools; C.H., Y.H., A.H., J.S., H.F., Y.F., Takehiro Suzuki,N.D., and Tadashi Suzuki analyzed data; and C.H. and Tadashi Suzuki wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.1To whom correspondence should be addressed. Email: [email protected].

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1414593112/-/DCSupplemental.

1398–1403 | PNAS | February 3, 2015 | vol. 112 | no. 5 www.pnas.org/cgi/doi/10.1073/pnas.1414593112

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Patient-led science

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computer science

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computer science

biology & medicine

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A drug discovery platform for NGLY1 deficiency

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YesReplicable?

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blog.might.net

http://blog.might.net
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Advocacy & Outreach

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Parting thought

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“not actionable”

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Thank you. http://matt.might.net/ [email protected] @mattmight


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