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  • 1. Aufschnaiter, Andreas
    et al.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Kohler, Verena
    Diessl, Jutta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Keller, Walter
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha-Synuclein Toxicity2017In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 207Article in journal (Refereed)
    Abstract [en]

    The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of alpha-synuclein (alpha Syn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of alpha Syn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca2+ homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear. Here, we establish a connection between the major lysosomal protease cathepsin D (CatD) and the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human alpha Syn triggered cytosolic acidification and reduced vacuolar hydrolytic capacity, finally leading to cell death. This could be counteracted by overexpression of yeast CatD (Pep4), which re-installed pH homeostasis and vacuolar proteolytic function, decreased alpha Syn oligomers and aggregates, and provided cytoprotection. Interestingly, these beneficial effects of Pep4 were independent of autophagy. Instead, they required functional calcineurin signaling, since deletion of calcineurin strongly reduced both the proteolytic activity of endogenous Pep4 and the cytoprotective capacity of overexpressed Pep4. Calcineurin contributed to proper endosomal targeting of Pep4 to the vacuole and the recycling of the Pep4 sorting receptor Pep1 from prevacuolar compartments back to the trans-Golgi network. Altogether, we demonstrate that stimulation of this novel calcineurin-Pep4 axis reduces alpha Syn cytotoxicity.

  • 2. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Walter, Corvin
    Tosal-Castano, Sergi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wolinski, Heimo
    Keller, Walter
    Vögtle, F-Nora
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondria Biogenesis in Aging Yeast2018In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 205Article in journal (Refereed)
    Abstract [en]

    Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson's disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondria! biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria-related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology.

  • 3.
    Kaimal, Jayasankar Mohanakrishnan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nuclear targeting of Hsp110 modifies the proteostasis system by mobilizing latent Hsp70 chaperonesManuscript (preprint) (Other academic)
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