Assistant Professor, Biochemistry and Molecular Biology
2010 B.S. Biochemistry, Central Michigan University, Mount Pleasant, Michigan
2015 Ph.D. Biochemistry, University of Michigan, Ann Arbor, Michigan
The Rauch lab is focused on understanding the cellular and molecular mechanisms that contribute to diseases associated with protein misfolding and aggregation - with a particular focus on the neurodegenerative protein tau. Tau is an abundant and highly soluble protein, yet is known to aggregate in a variety of diseases, including Alzheimer’s Disease. The deposition of tau aggregates, or neurofibrillary tangles (NFTs), is correlated with cognitive decline in patients and permits neuropathological diagnoses of patients in different stages of disease. While the composition and structure of NFTs are well-characterized, the in vivo process of tau aggregation and the subsequent spread of this aggregation are not well understood phenomena.
The lab is focused on three main areas of research in regards to tau neurobiology: tau spread mechanisms, tau physical state transitions, and the influence of cellular identity on disease mechanism. The overarching goal of the lab is to understand the requirements for tau disease progression and to devise new strategies to treat disease. We use a variety of techniques in the lab (in vitro biochemistry, single cell RNA sequencing, CRISPR-based functional genomics, optogenetic technologies, etc.) across different system models (cell lines, differentiated stem cells, primary cultures, and mice) in order to build a complete picture of tau regulation.
1. Miyata Y*, Rauch JN*, Jinwal UK, Thompson AD, Srinivasan S, Dickey CA, Gestwicki JE. Cysteine reactivity distinguishes redox sensing by the heat-inducible and constitutive forms of
heat shock protein 70. Chemistry & Biology. 2012; 19:1391-9. (*co-first author)
2. Assimon VA*, Gilles AT*, Rauch JN*, Gestwicki JE. Hsp70 protein complexes as drug targets. Current Pharmaceutical Design. 2013; 19(3):404-17. (*co-first authors)
3. Rauch JN*, Nie J*, Buchholz TJ, Gestwicki JE, Kennedy RT. Development of a capillary electrophoresis platform for identifying inhibitors of protein-protein interactions. Analytical Chemistry. 2013; 85(20):9824-31. (*co-first authors)
4. Rauch JN and Gestwicki JE. Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro. Journal of Biological Chemistry. 2014; 289(3):1402-14.
5. Colvin TA, Gabai VL, Gong J, Calderwood SK, Li H, Gummuluru S, Matchuk OH, Smirnov SG, Orlova NV, Zamulaeva IA, Garcia-Marcos M, Li X, Young ZT, Rauch JN, Gestwicki JE, Takayama S, Sherman MY. Hsp70-Bag3 Interactions Regulate Cancer-Related Signaling Networks. Cancer Research. 2014; 74(17):1-10.
6. Rauch JN and Geswicki JE. Rehabilitating Mutant GCase. Chemistry & Biology. 2014; 21(8):919-20.
7. Li X, Colvin TA, Rauch JN, Acosta-Alvear D, Kampmann M, Dunyak B, Hann B, Aftab BT, Murnane MR, Cho M, Walter P, Weissman JS, Sherman MY, Gestwicki JE. Validation of the Hsp70-Bag3 Protein-Protein Interaction as a Potential Therapeutic Target in Cancer. Molecular Cancer Therapeutics. 2015; 14(3):642-8.
8. Rauch, JN. “Heat Shock Protein 110.” StressMarq Biosciences Inc. http://hsp110.com (under construction)
9. Fontaine SN, Rauch JN, Nordhues BA, Assimon VA, Stothert AR, Jinwal UK, Sabbagh JJ, Chang L, Stevens SM Jr, Zuiderweg ER, Gestwicki JE, Dickey CA. Isoform Selective Genetic Inhibition of Constitutive Cytosolic Hsp70 Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement. Journal of Biological Chemistry. 2015; 290(21):13115-27.
10. Taguwa S, Maringer K, Li X, Bernal-Rubio D, Rauch JN, Gestwicki JE, Andino R, Fernandez- Sesma A, Frydman J. Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection. Cell. 2015; 163(5):1108-23.
11. Morozova K, Clement CC, Kaushik S, Stiller B, Arias E, Ahmad A, Rauch JN, Chatterjee V, Melis C, Scharf B, Gestwicki JE, Cuervo AM, Zuiderweg ERP, Santambrogio L. Structural and Biological Interaction of hsc-70 Protein with Phosphatidylserine in Endosomal Microautophagy. Journal of Biological Chemistry 2016; 291(35):18096-106.
12. Ouimet CM, Shao H, Rauch JN, Dawod M, Nordhues B, Dickey CA, Gestwicki JE, Kennedy RT. Protein Cross-linking Capillary Electrophoresis (PXCE) for Protein-Protein Interaction Analysis. Analytical Chemistry. 2016; 88(16):8272-8.
13. Rauch JN, Zuiderweg ERP, Gestwicki JE. Non-Canonical Interactions Between Heat Shock Cognate Protein 70 (Hsc70) and the Bcl2-Associated Anthanogene (BAG) Family of Co-Chaperones are Important for Client Release. Journal of Biological Chemistry. 2016; 291(38):19848-57.
14. Young ZT, Rauch JN, Assimon VA, Jinwal UK, Li X, Dunyak BM, Ahmad A, Carlson GA, Srinivasan SR, Zuiderweg ERP, Dickey CA, Gestwicki JE. Stabiling the Hsp70-tau complex promotes turnover in a model of tauopathy. Cell Chem Biol. 2016; 23:561-566
15. Rauch JN, Olson SH, Gestwicki JE. Interactions Between Microtubule-Binding Protein Tau (MAPT) and small molecules. Cold Spring Harb Perspect Med. 2017; 7(7): a024034
16. Rauch JN, Tse E, Makley LN, Freilich R, Southworth DR, Gestwicki JE. BAG3 is a modular scaffolding protein that physically links heat shock protein 70 (Hsp70) to the small heat shock proteins. Journal of Molecular Biology. 2017; 429(1): 128-41.
17. Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS, Han S. RNA stores tau reversibly in complex coacervates. PLoS Biology. 2017; 15(7): e2002183
18. Taylor IR, Dunyak BM, Komiyama T, Shao H, Ran X, Assimon VA, Kalyanaraman DC, Rauch JN, Jacobson MP, Zuiderweg ERP, Gestwicki JE. High Throughput Screen for Inhibitors of Protein-Protein Interactions in a Reconstituted Heat Shock Protein 70 (Hsp70) Complex. Journal of Biological Chemistry. 2018; 293(11):4014-4025.
19. Mok SA, Condello C, Freilich R, Gillies A, Arhar T, Oroz J, Kadavath H, Julien O, Assimon VA, Rauch JN, Dunyak BM, Lee J, Tsai FTF, Wilson MR, Zweckstetter M, Dickey CA, Gestwicki JE. Mapping Interactions with the Chaperone Network Reveals Factors that Protect Against Tau Aggregation. Nature Structural & Molecular Biology. 2018; 25(5):384-393.
20. Rauch JN, Chen JJ, Sorum A, Miller GM, Sharf T, See SK, Hsieh-Wilson LC, Kampmann M, Kosik KS. Tau internalization is regulated by 6-O sulfation on Heparan Sulfate Proteoglycans (HSPGs). Scientific Reports. 2018; 8(1): 6382.
21. Meister-Broekema M*, Freilich R*, Jagadeesan C*, Rauch JN*, Bengoechea R, Motley WW, Kuiper EFE, Minoia M, Furtado GV, Van Waarde MAWH, Bird SJ, Rebelo A, Zuchner S, Pytel P, Scherer SS, Carra S, Weihl CC, Bergink S, Gestwicki JE, Kampinga HH. Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nature Communications. 2018; 9(1):5342. (*co-first authors)
22. Fichou Y*, Lin Y*, Rauch JN, Vigers M, Kosik KS, Han S. Cofactors are essential consituents of stable and seeding-active tau fibrils. PNAS. 2018; 115(52): 13234-13239.
23. Hernandez I*, Luna G*, Rauch JN, Reis SA, Giroux M, Karch CM, Boctor D, Sibih YE, Storm NJ, Diaz A, Kaushik S, Zekanowski C, Kang AA, Hinman CR, Cerovac V, Guzman E, Zhou H, Haggarty SJ, Goate AM, Fisher SK, Cuervo AM, Kosik KS. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Science Translational Medicine. 2019; 11(485). pii: eaat3005.
24. Lin Y*, McCarty J*, Rauch JN, Kosik KS, Fredrickson GH, Shea JE, Han S. Narrow equilibrium window for the complex coacervation of tau and RNA under cellular conditions. eLife. 2019; pii: e42571.
25. Eftekharzadeh B*, Banduseela VC*, Chiesa G*, Martinez-Cristobal P, Rauch JN, Schwarz DMC, Shao H, Marin-Argany M, Di Sanza C, Giorgetti E, Yu Z, Pieratelli R, Felli IC, Brun-Heath I, Garcia J, Nebreda AR, Gestwicki JE, Lieberman AP, Salvatella X. Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor. Nature Communications. 2019; 10(1): 3562.
26. Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, Gradinaru V, Kampmann M, Kosik KS. LRP1 is a master regulator of tau uptake and spread. Nature. 2020; 580: 381–385.
27. Zhang X, Vigers M, McCarty J, Rauch JN, Fredrickson GH, Wilzon MZ, Shea JE, Han S, Kosik KS. The proline-rich domain promotes tau liquid liquid phase separation in cells. (under review)
28. Lin Y, Fichou Y, Rauch JN, Kosik KS, Han S. Mapping phase diagram of tau-RNA LLPS under live cell coculturing conditions. Methods in Molecular Biology (invited chapter, under review).
29. Rauch JN*, Valois E*, Solley SC, Braig F, Lach RS, Audouard M, Baxter NJ, Kosik KS, Arias C, Acosta-Alvear D, Wilson MZ. A Scalable, Easy-to-Deploy, Protocol for Cas13-Based Detection of SARS-CoV-2 Genetic Material. (submitted). Preprint - biorxiv.org (https://www.biorxiv.org/content/10.1101/2020.04.20.052159v1)
30. Rauch JN, Ponce JC, Valois E, Zappa F, Audouard M, Lach RS, Aralis Z, Solley SC, Kosik KS, Acosta-Alvear D, Wilson MZ, Arias C. Surveillance of COVID-19 prevalence in the Santa Barbara Community. (in preparation)