WashU weekly Neuroscience publications

Genome-wide association study and functional validation implicates JADE1 in tauopathy
(2021) Acta Neuropathologica, . 

Farrell, K.^a b c , Kim, S.H.^a b c , Han, N.^a b c , Iida, M.A.^a b c , Gonzalez, E.M.^d , Otero-Garcia, M.^e , Walker, J.M.^f , Richardson, T.E.^f , Renton, A.E.^b g , Andrews, S.J.^b g , Fulton-Howard, B.^b g , Humphrey, J.^b g , Vialle, R.A.^b g , Bowles, K.R.^g , de Paiva Lopes, K.^b g , Whitney, K.^a b c , Dangoor, D.K.^a b c , Walsh, H.^a b c , Marcora, E.^b g , Hefti, M.M.^h , Casella, A.^a b c , Sissoko, C.T.^a b c , Kapoor, M.^b g , Novikova, G.^b g , Udine, E.^b g , Wong, G.^b g , Tang, W.^ae , Bhangale, T.ⁱ , Hunkapiller, J.ⁱ , Ayalon, G.^j , Graham, R.R.^k , Cherry, J.D.^l , Cortes, E.P.^a b , Borukov, V.Y.^a b , McKee, A.C.^l , Stein, T.D.^l , Vonsattel, J.-P.^m , Teich, A.F.^m , Gearing, M.ⁿ , Glass, J.ⁿ , Troncoso, J.C.^o , Frosch, M.P.^p , Hyman, B.T.^p , Dickson, D.W.^q , Murray, M.E.^q , Attems, J.^r , Flanagan, M.E.^s , Mao, Q.^s , Mesulam, M.-M.^s , Weintraub, S.^s , Woltjer, R.L.^t , Pham, T.^t , Kofler, J.^u , Schneider, J.A.^v , Yu, L.^v , Purohit, D.P.^a w , Haroutunian, V.^b w , Hof, P.R.^b , Gandy, S.^w am , Sano, M.^w , Beach, T.G.^x , Poon, W.^y , Kawas, C.H.^an , Corrada, M.M.^y , Rissman, R.A.^z , Metcalf, J.^z , Shuldberg, S.^z , Salehi, B.^z , Nelson, P.T.^aa , Trojanowski, J.Q.^ab , Lee, E.B.^ab , Wolk, D.A.^ac , McMillan, C.T.^ac , Keene, C.D.^ad , Latimer, C.S.^ad , Montine, T.J.^ad ae , Kovacs, G.G.^af ag ah , Lutz, M.I.^ah , Fischer, P.^ao , Perrin, R.J.^ai , Cairns, N.J.^al , Franklin, E.E.^ai , Cohen, H.T.^aj , Raj, T.^b g , Cobos, I.^ae , Frost, B.^d , Goate, A.^b g , White III, C.L.^ak , Crary, J.F.^a b c

^a Department of Pathology, Neuropathology Brain Bank and Research CoRE, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place Box 1194, New York, NY 10029, United States
^b Nash Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^c Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Cell Systems and Anatomy, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, the Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX 78229, United States
^e Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California, Los Angeles, CA, United States
^f Department of Pathology and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, United States
^g Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^h Department of Pathology, University of Iowa, Iowa City, IA, United States
ⁱ Department of Human Genetics, Genentech, South San Francisco, CA, United States
^j Neumora Therapeutics, South San Francisco, CA, United States
^k Maze Therapeutics, San Francisco, CA, United States
^l Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, United States
^m Department of Pathology and Cell Biology, Department of Neurology, and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
ⁿ Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, United States
^o Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^p Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, United States
^q Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
^r Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
^s Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^t Department of Pathology, Oregon Health Sciences University, Portland, OR, United States
^u Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^v Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^w Department of Psychiatry, Alzheimer’s Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^x Department of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, United States
^y Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, United States
^z Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, CA, United States
^aa Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
^ab Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ac Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ad Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, United States
^ae Department of Pathology, Stanford University, Palo Alto, United States
^af Laboratory Medicine Program, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
^ag Tanz Centre for Research in Neurodegenerative Disease and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
^ah Institute of Neurology, Medical University of Vienna, Vienna, Austria
^ai Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^aj Departments of Medicine, Pathology, and Pharmacology, Boston University School of Medicine and Boston Medical Center, Boston, MA, United States
^ak Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, United States
^al College of Medicine and Health, University of Exeter, Exeter, United Kingdom
^am Department of Neurology, Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^an Department of Neurology, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, United States
^ao Department of Psychiatry, Danube Hospital, Vienna, Austria

Abstract
Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts
(2021) Journal of Lipid Research, 63, art. no. 100114, . 

Pipalia, N.H.^a , Saad, S.Z.^a , Subramanian, K.^b , Cross, A.^c , al-Motawa, A.^a , Garg, K.^a , Blagg, B.S.J.^d , Neckers, L.^e , Helquist, P.^d , Wiest, O.^d , Ory, D.S.^b , Maxfield, F.R.^a

^a Department of Biochemistry, Weill Cornell Medical College, New York, NY, United States
^b Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Natural Sciences Department, Fordham University, New York, NY, United States
^d Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, United States
^e Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, United States

Abstract
Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids, and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. The increase in other chaperones as a consequence of HSP90 improves folding of NPC1 protein and relieves cholesterol accumulation in NPC1 mutant fibroblasts. © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.

Author Keywords
Arimoclomol;  Chaperone;  Cholesterol;  Drug therapy;  Endocytosis;  Fluorescence microscopy;  HSP70;  HSP90;  Lysosomal storage;  Niemann-Pick disease

Glycine-Rich Peptides from FUS Have an Intrinsic Ability to Self-Assemble into Fibers and Networked Fibrils
(2021) Biochemistry, . 

Kar, M.^a , Posey, A.E.^b , Dar, F.^c , Hyman, A.A.^a , Pappu, R.V.^b

^a Max Planck Institute of Cell Biology and Genetics (MPI-CBG), Dresden, 01307, Germany
^b Dept. of Biomedical Engineering and Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, United States
^c Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Glycine-rich regions feature prominently in intrinsically disordered regions (IDRs) of proteins that drive phase separation and the regulated formation of membraneless biomolecular condensates. Interestingly, the Gly-rich IDRs seldom feature poly-Gly tracts. The protein fused in sarcoma (FUS) is an exception. This protein includes two 10-residue poly-Gly tracts within the prion-like domain (PLD) and at the interface between the PLD and the RNA binding domain. Poly-Gly tracts are known to be highly insoluble, being potent drivers of self-assembly into solid-like fibrils. Given that the internal concentrations of FUS and FUS-like molecules cross the high micromolar and even millimolar range within condensates, we reasoned that the intrinsic insolubility of poly-Gly tracts might be germane to emergent fluid-to-solid transitions within condensates. To assess this possibility, we characterized the concentration-dependent self-assembly for three non-overlapping 25-residue Gly-rich peptides derived from FUS. Two of the three peptides feature 10-residue poly-Gly tracts. These peptides form either long fibrils based on twisted ribbon-like structures or self-supporting gels based on physical cross-links of fibrils. Conversely, the peptide with similar Gly contents but lacking a poly-Gly tract does not form fibrils or gels. Instead, it remains soluble across a wide range of concentrations. Our findings highlight the ability of poly-Gly tracts within IDRs that drive phase separation to undergo self-assembly. We propose that these tracts are likely to contribute to nucleation of fibrillar solids within dense condensates formed by FUS. © 2021 American Chemical Society.

Funding details
National Institutes of HealthNIH5R01056114
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Human Frontier Science ProgramHFSPRGP0034/2017
Max-Planck-GesellschaftMPG
NOMIS Stiftung