Pink1-SNCA çift mutant Parkinson farelerinde erken prodromal duyusal nöropati

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Abstract BACKGROUND: Parkinson's Disease (PD) is frequently associated with a prodromal sensory neuropathy, which manifests as sensory loss and eventually chronic pain. METHODS: The present study assessed somatosensory functions and the pathology of somatosensory neurons in Pink1-/-SNCAA53T double mutant mice (Pink1SNCA) who develop a PD-like disease > 15 months of age. RESULTS: Pink1SNCA mice showed the first manifestations of sensory dysfunctions at 6 months of age, which were characterized by a loss of thermal sensitivity but sparing of mechanical sensation, and decline of olfactory perception of pleasant odors. Mechanistically, the loss of thermal sensitivity was attributed to a strong reduction of transient receptor potential TRPV and TRPA channels at mRNA, protein and functional levels in the dorsal root ganglia (DRGs). Primary sensory neurons responded much less to stimulations with capsaicin, formalin or depolarization as assessed by calcium imaging. RNA sequencing pointed to additional deregulations of voltage dependent potassium channel subtypes, lowering of acidic fibroblast growth factor driven support, and alterations of sphingolipid metabolism. Analyses of sphingolipids of multiple classes revealed an accumulation of glucosylceramides mainly in the DRGs and loss of sphingosines and sphinganines in the sciatic nerve. Transmission electron microscopy of the DRGs revealed a higher frequency of neurons with swollen mitochondria, which was associated with a decrease of mitochondrial respiration in sensory ganglia, but not in the brain. CONCLUSION: The data support the view of a prodromal sensory disease in PD resulting from a combination of lipid allostasis and mitochondrial damage. Hence, Pink1SNCA mice phenocopy the PD-associated prodromal sensory neuropathy and reveal novel mechanistic insight.

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