Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>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 <jats:italic>Pink1</jats:italic><jats:sup>−/−</jats:sup><jats:italic>SNCA<jats:sup>A53T</jats:sup></jats:italic> double mutant mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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 <jats:italic>Pink1</jats:italic><jats:sup>−/−</jats:sup><jats:italic>SNCA<jats:sup>A53T</jats:sup></jats:italic> double mutant mice beyond 15 months of age.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Similar to PD patients, <jats:italic>Pink1</jats:italic><jats:sup>−/−</jats:sup><jats:italic>SNCA<jats:sup>A53T</jats:sup></jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>