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Psychosis ‐Like Behavior andHyperdopaminergic Dysregulation inHuman α‐Synuclein BAC Transgenic Rats Polissidis, Alexia; Koronaiou, Maria; Kollia, Vasia; Koronaiou, Effrosyni; Nakos‐Bimpos, Modestos; Bogiongko, Marios; Vrettou, Sofia; Karali, Katerina; Casadei, Nicolas; Riess, Olaf; Sardi, Sergio P.; Xilouri, Maria; Stefanis, Leonidas
Movement disorders, March 2021, 2021-03-00, 20210301, Letnik: 36, Številka: 3Journal Article
Background Parkinson's disease psychosis is a prevalent yet underreported and understudied nonmotor manifestation of Parkinson's disease and, arguably, the most debilitating. It is unknown if α‐synuclein plays a role in psychosis, and if so, this endophenotype may be crucial for elucidating the neurodegenerative process. Objectives We sought to dissect the underlying neurobiology of novelty‐induced hyperactivity, reminiscent of psychosis‐like behavior, in human α‐synuclein BAC rats. Results Herein, we demonstrate a prodromal psychosis‐like phenotype, including late‐onset sensorimotor gating disruption, striatal hyperdopaminergic signaling, and persistent novelty‐induced hyperactivity (up to 18 months), albeit reduced baseline locomotor activity, that is augmented by d‐amphetamine and reversed by classical and atypical antipsychotics. MicroRNA‐mediated α‐synuclein downregulation in the ventral midbrain rescues the hyperactive phenotype and restores striatal dopamine levels. This phenotype is accompanied by an abundance of age‐, brain region– and gene dose–dependent aberrant α‐synuclein, including hyperphosphorylation, C‐terminal truncation, aggregation pathology, and mild nigral neurodegeneration (27%). Conclusions Our findings demonstrate a potential role of α‐synuclein in Parkinson's disease psychosis and provide evidence of region‐specific perturbations prior to neurodegeneration phenoconversion. The reported phenotype coincides with the latest clinical findings that suggest a premotor hyperdopaminergic state may occur, while at the same time, premotor psychotic symptoms are increasingly being recognized. © 2020 International Parkinson and Movement Disorder Society
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