Τίτλος:
Psychosis-Like Behavior and Hyperdopaminergic Dysregulation in Human α-Synuclein BAC Transgenic Rats
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020 International Parkinson and Movement Disorder Society
Συγγραφείς:
Polissidis, A.
Koronaiou, M.
Kollia, V.
Koronaiou, E.
Nakos-Bimpos, M.
Bogiongko, M.
Vrettou, S.
Karali, K.
Casadei, N.
Riess, O.
Sardi, S.P.
Xilouri, M.
Stefanis, L.
Περιοδικό:
Movement Disorders
Εκδότης:
John Wiley and Sons Inc
Λέξεις-κλειδιά:
3 o methyldopamine; 3,4 dihydroxyphenylacetic acid; 5 hydroxyindoleacetic acid; alpha synuclein; clozapine; dexamphetamine; dopamine; haloperidol; homovanillic acid; microRNA; noradrenalin; pimavanserin; serotonin; alpha synuclein, age; animal experiment; animal model; animal tissue; Article; behavior assessment; brain region; carboxy terminal sequence; controlled study; corpus striatum; down regulation; female; frontal cortex; gene dosage; genotype; hippocampus; hyperactivity; locomotion; low drug dose; male; nerve degeneration; nonhuman; Parkinson disease; phenotype; priority journal; prodromal symptom; protein expression; protein phosphorylation; psychosis; rat; sensory gating; sex difference; substantia nigra; transgenic rat; ventral mesencephalon; animal; disease model; genetics; human; metabolism; mouse; psychosis; transgenic mouse, alpha-Synuclein; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Parkinson Disease; Psychotic Disorders; Rats; Rats, Transgenic; Substantia Nigra
