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The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondria Biogenesis in Aging Yeast
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
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Antal upphovsmän: 92018 (Engelska)Ingår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, artikel-id 205Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
2018. Vol. 11, artikel-id 205
Nyckelord [en]
LRRK2, Parkinson's disease, neurodegeneration, mitochondria, complex IV, cell death, yeast, aging
Nationell ämneskategori
Biologiska vetenskaper Neurovetenskaper
Identifikatorer
URN: urn:nbn:se:su:diva-158246DOI: 10.3389/fnmol.2018.00205ISI: 000435852400001PubMedID: 29977190OAI: oai:DiVA.org:su-158246DiVA, id: diva2:1238253
Tillgänglig från: 2018-08-13 Skapad: 2018-08-13 Senast uppdaterad: 2018-08-13Bibliografiskt granskad

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Av författaren/redaktören
Aufschnaiter, AndreasKohler, VerenaTosal-Castano, SergiHabernig, LukasBüttner, Sabrina
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Institutionen för molekylär biovetenskap, Wenner-Grens institut
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Frontiers in Molecular Neuroscience
Biologiska vetenskaperNeurovetenskaper

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