Cognitive dysfunction precedes the onset of motor symptoms in the MitoPark mouse

More evidence that cognitive impairment may be an early feature in Parkinson's Disease.  The MitoPark mouse model of Parkinson's disease was developed in response to the finding that dopaminergic neurons in Parkinson's patients often have mutations in mitochondrial DNA. Whilst these changes have not been shown to cause Parkinson's, so-called MitoPark mice, which have mutations in the gene for mitochondrial transcription factor, show motor features of Parkinson's disease. More interestingly, they also show Parkinson's-like pathology, with intraneuronal inclusions and domamine cell death. Here, researchers have shown that these mice were impaired on a test of spatial learning and object recognition at 8 weeks, whilst difficulties with movement were not seen until 12 weeks. 

Many questions remain regarding whether this model truly represents Parkinson's disease, whether there are early subtle motor changes that were not picked up and the around the validity of cognitive tests in mice. However, there is a glimmer of hope that model will give us the opportunity to understand much more about the neural basis of cognitive dysfunction in Parkinson's. 

-Anna

PLoS One. 2013 Aug 15;8(8):e71341. doi: 10.1371/journal.pone.0071341.

Cognitive dysfunction precedes the onset of motor symptoms in the MitoPark mouse 

model of Parkinson's disease.

Li X, Redus L, Chen C, Martinez PA, Strong R, Li S, O'Connor JC.

Department of Pharmacology, The University of Texas Health Science Center, San

Antonio, Texas, United States of America ; Department of Medicine, The University

of Texas Health Science Center, San Antonio, Texas, United States of America ;

Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong

University, Jinan, P.R. China.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized 

by progressive loss of dopamine neurons, leading to loss of motor coordination.

However, PD is associated with a high rate of non-motor neuropsychiatric

comorbities that often develop before the onset of movement symptoms. The

MitoPark transgenic mouse model is the first to recapitulate the cardinal

clinical features, namely progressive neurodegeneration and death of neurons,

loss of motor function and therapeutic response to L-DOPA. To investigate whether

MitoPark mice exhibit early onset of cognitive impairment, a non-motor

neuropsychiatric comorbidity, we measured performance on a spatial learning and

memory task before (∼8 weeks) or after (∼20 weeks) the onset of locomotor decline

in MitoPark mice or in littermate controls. Consistent with previous studies, we 

established that a progressive loss of spontaneous locomotor activity began at 12

weeks of age, which was followed by progressive loss of body weight beginning at 

16-20 weeks. Spatial learning and memory was measured using the Barnes Maze. By

20 weeks of age, MitoPark mice displayed a substantial reduction in overall

locomotor activity that impaired their ability to perform the task. However, in

the 8-week-old mice, locomotor activity was no different between genotypes, yet

MitoPark mice took longer, traveled further and committed more errors than same

age control mice, while learning to successfully navigate the maze. The modest

between-day learning deficit of MitoPark mice was characterized by impaired

within-day learning during the first two days of testing. No difference was

observed between genotypes during probe trials conducted one or twelve days after

the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited

impaired novel object recognition when compared to control mice. Together, these 

data establish that mild cognitive impairment precedes the loss of motor function

in a novel rodent model of PD, which may provide unique opportunities for

therapeutic development.

PMCID: PMC3744561

PMID: 23977020  [PubMed - in process]