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- Kohler, Andreas, Dr. rer. nat. 1988-, et al.
(författare)
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The enzymatic core of the Parkinson’s disease-associated protein LRRK2 impairs mitochondrial biogenesis in aging yeast
- 2018
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media S.A.. - 1662-5099. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- 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 mitochondrial 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.
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| 2. |
- Kohler, Verena, 1992-, et al.
(författare)
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TraN: A novel repressor of an Enterococcus conjugative type IV secretion system
- 2018
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 46:17, s. 9201-9219
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Tidskriftsartikel (refereegranskat)abstract
- The dissemination of multi-resistant bacteria represents an enormous burden on modern healthcare. Plasmid-borne conjugative transfer is the most prevalent mechanism, requiring a type IV secretion system that enables bacteria to spread beneficial traits, such as resistance to last-line antibiotics, among different genera. Inc18 plasmids, like the Gram-positive broad host-range plasmid pIP501, are substantially involved in propagation of vancomycin resistance from Enterococci to methicillin-resistant strains of Staphylococcus aureus. Here, we identified the small cytosolic protein TraN as a repressor of the pIP501-encoded conjugative transfer system, since deletion of traN resulted in upregulation of transfer factors, leading to highly enhanced conjugative transfer. Furthermore, we report the complex structure of TraN with DNA and define the exact sequence of its binding motif. Targeting this protein–DNA interaction might represent a novel therapeutic approach against the spreading of antibiotic resistances.
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