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Prodromal sensory neuropathy in Pink1-/-SNCAA53T double mutant Parkinson mice

  • Aims: Parkinson's disease (PD) is frequently associated with a prodromal sensory neuropathy manifesting with sensory loss and chronic pain. We have recently shown that PD-associated sensory neuropathy in patients is associated with high levels of glucosylceramides. Here, we assessed the underlying pathology and mechanisms in Pink1−/−SNCAA53T double mutant mice. Methods: We studied nociceptive and olfactory behaviour and the neuropathology of dorsal root ganglia (DRGs), including ultrastructure, mitochondrial respiration, transcriptomes, outgrowth and calcium currents of primary neurons, and tissue ceramides and sphingolipids before the onset of a PD-like disease that spontaneously develops in Pink1−/−SNCAA53T double mutant mice beyond 15 months of age. Results: Similar to PD patients, Pink1−/−SNCAA53T mice developed a progressive prodromal sensory neuropathy with a loss of thermal sensitivity starting as early as 4 months of age. In analogy to human plasma, lipid analyses revealed an accumulation of glucosylceramides (GlcCer) in the DRGs and sciatic nerves, which was associated with pathological mitochondria, impairment of mitochondrial respiration, and deregulation of transient receptor potential channels (TRPV and TRPA) at mRNA, protein and functional levels in DRGs. Direct exposure of DRG neurons to GlcCer caused transient hyperexcitability, followed by a premature decline of the viability of sensory neurons cultures upon repeated GlcCer application. Conclusions: The results suggest that pathological GlcCer contribute to prodromal sensory disease in PD mice via mitochondrial damage and calcium channel hyperexcitability. GlcCer-associated sensory neuron pathology might be amenable to GlcCer lowering therapeutic strategies.
Metadaten
Author:Lucie Valek, Bao Tran, Annett Wilken-Schmitz, Sandra Trautmann, Juliana HeidlerORCiD, Tobias Schmid, Bernhard BrüneORCiD, Dominique Jeanette ThomasORCiDGND, Thomas Deller, Gerd GeisslingerORCiDGND, Georg AuburgerORCiDGND, Irmgard TegederORCiD
URN:urn:nbn:de:hebis:30:3-638974
DOI:https://doi.org/10.1111/nan.12734
ISSN:1365-2990
Parent Title (English):Neuropathology & applied neurobiology
Publisher:Wiley-Blackwell
Place of publication:Oxford [u.a.]
Document Type:Article
Language:English
Date of Publication (online):2021/05/11
Date of first Publication:2021/05/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/04/05
Tag:PTEN inducible kinase 1; Parkinson's disease; alpha-synuclein; glucosylceramides; innate immunity; mitochondrial respiration; pain; sensory loss
Volume:47
Issue:7
Page Number:20
First Page:1060
Last Page:1079
Note:
The study was supported by the Deutsche Forschungsgemeinschaft CRC1039 (A03 to IT; Z1 to GG), CRC1080 (C02 to IT, B03 to TD), SFB815 (A12 to IT; A08 to BB; Z1 to JH) and by the Fraunhofer Cluster of Excellence for immune mediated diseases (CIMD, to GG).
Note:
The peer review history for this article is available at https://publons.com/publon/10.1111/nan.12734.
HeBIS-PPN:493745025
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0