Characterization of Nonmotor Symptoms in the MitoPark Mouse Model of Parkinson’s Disease

Abstract

Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson's disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since non-motor symptoms are now recognized as important features of the prodromal stage of PD, we monitored the clinically relevant motor and nonmotor symptoms from ages 8-24 wks in MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wks and became severe by 16-24 wks. Interestingly, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wks and becoming most severe at 16 wks, as determined by Morris water maze. When compared to age-matched control mice, MitoPark mice exhibited olfactory deficits in novel and social scent tests as early as 10-12 wks. MitoPark mice between 16-24 wks spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in cognitive learning and memory, olfactory discrimination, and anxiety- and depression-like behaviors. Thus, MitoPark mice can serve as an invaluable model for studying motor and non-motor symptoms in addition to studying pathology in PD.

Mechanisms of Sleep/Wake Regulation under Hypodopaminergic State: Insights from MitoPark Mouse Model of Parkinson's Disease

“…Similar to PD patients, recent studies have also documented several NMS in MitoPark mice. [ 83 ] In addition to these features, our study reveals a high face validity of MitoPark mice in replicating most sleep alterations experienced by PD patients. The lack of RBD in MitoPark mice is consistent with the non‐DAergic pathophysiological mechanism behind RBD recently shown in several neurocircuit investigations.…”

“…Consistent with the role of midbrain DA in modulating mood, [ 80–82 ] neurodegeneration of DA neurons in MitoPark mice induces anxiety and depression. [ 83 ] The dominance of these depressive moods during wake in MitoPark mice might therefore explain their hypersomnia phenotype. This pathophysiological mechanism could also explain the dramatic decrease of REM sleep in MitoPark mice given the impact of negative valence (i.e., CD‐1 male exposure) on REM sleep (Figure S7, Supporting Information).…”

Impact of unconventional Ω-3 sources on cognitive development: A nexus to explore for future brains

“…1). Based on findings that antioxidants and αtocopherol exacerbated the impacts of the nutrition, elevated OS may facilitate the impact of the nutrition on plasticity (Langley 2017).…”