Cellular factors implicated in amyloid fibril homeostasis
Final Report Abstract
Tauopathies such as Alzheimer’s disease, frontotemporal dementia with Parkinsonism and other neurodegenerative disorders are characterized by the spread of tau pathology from an initial brain region to neuroanatomically connected areas. At the molecular level, spreading involves aggregation of tau in an initial cell, externalization of transmittable fragments of amyloid fibrils, internalization in a recipient cell followed by seeding of endogenous tau. However, the response of the protein quality control system to tau pathology and in particular to the spreading process is not well understood. In particular, a co-migrating factor performing location-independent interference of fibril formation and transmission would be an appropriate conceptual solution. Our data show that the cell-to-cell transmission of the widely conserved serine protease HTRA1 impedes tau spreading by targeting multiple steps within the process. Our results suggest a defence mechanism against the intercellular spread of pathogenic protein conformations. To understand the proteolysis of fibrils by HTRA1 at high spatial and temporal resolution, we used time-resolved mass spectrometry in combination with bioinformatic analyses to identify up to 200 proteolytic products and to calculate the relative frequency of cuts at each of the identified 117 cleavage sites at each time point. Interestingly, the b-sheet-rich core region of fibrils is degraded into 30 peptides after 10 min of incubation, even when the fibrils are present in a five-fold molar access of the protease. Zymogen activation is a widely conserved regulatory principle across protease clans. It describes the irreversible activation by processing of the inactive zymogen precursor by an active protease. We report an alternative and reversible mechanism of protease activation, where the activator is an inactive protease. This mechanism involves the formation of an allosteric complex between the serine PDZ protease HTRA1 and the cysteine protease calpain 2. Surprisingly, the allosteric activation of HTRA1 is restricted to a subset of substrate conformations as it improves the proteolysis of soluble tau protein but not the dissociation and degradation of amyloid fibrils. These data exemplify an additional challenge for protein quality control factors such as HTRA1 in the clearing of pathogenic fibrils.
Publications
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EP 3280801B1; "Internalisation of human HTRA1 and cargo proteins into mammalian cells"
Ehrmann M.; Poepsel, S.; Nelles, J. & Severin, K.
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Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator. Journal of the American Society for Mass Spectrometry, 30(1), 16-23.
Nshanian, Michael; Lantz, Carter; Wongkongkathep, Piriya; Schrader, Thomas; Klärner, Frank-Gerrit; Blümke, Anika; Despres, Clément; Ehrmann, Michael; Smet-Nocca, Caroline; Bitan, Gal & Loo, Joseph A.
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The ubiquitin‐conjugating enzyme UBE 2 QL 1 coordinates lysophagy in response to endolysosomal damage. EMBO reports, 20(10).
Koerver, Lisa; Papadopoulos, Chrisovalantis; Liu, Bin; Kravic, Bojana; Rota, Giulia; Brecht, Lukas; Veenendaal, Tineke; Polajnar, Mira; Bluemke, Anika; Ehrmann, Michael; Klumperman, Judith; Jäättelä, Marja; Behrends, Christian & Meyer, Hemmo
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An allosteric HTRA1-calpain 2 complex with restricted activation profile. Proceedings of the National Academy of Sciences, 119(14).
Rey, Juliana; Breiden, Maike; Lux, Vanda; Bluemke, Anika; Steindel, Maike; Ripkens, Kamilla; Möllers, Bastian; Bravo, Rodriguez Kenny; Boisguerin, Prisca; Volkmer, Rudolf; Mieres-Perez, Joel; Clausen, Tim; Sanchez-Garcia, Elsa & Ehrmann, Michael
