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MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.

ABSTRACT: The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson's disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postural instability in PD. L-DOPA induces different locomotor responses depending on the age: in young MitoPark mice the L-DOPA-induced motor activation is small; middle-aged MitoPark mice respond in a dose-dependent manner to L-DOPA, whereas aged MitoPark mice display a double-peaked locomotor response to a high dose of L-DOPA that includes an intermittent period of very low motor activity, similar to the 'on-off' phenomenon in PD. To correlate behavior with biochemical data, we analyzed monoamine levels in three different brain areas that are highly innervated by the DA system: striatum, anterior cortex and olfactory bulb. DA levels declined earlier and faster in striatum than in cortex; only at the latest time-point analyzed, DA levels were found to be significantly lower than control levels in the olfactory bulb. Interestingly, the ratio between homovanillic acid (HVA) and DA differed between regions over time. In striatum and olfactory bulb, the ratio increased steeply indicating increased DA turnover. In contrast, the ratio decreased over time in cortex, revealing important differences between DA cells in substantia nigra and the ventral tegmental area.

SUBMITTER: Galter D

PROVIDER: S-EPMC4154513 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.

Galter D D Pernold K K Yoshitake T T Lindqvist E E Hoffer B B Kehr J J Larsson N-G NG Olson L L

Genes, brain, and behavior 20091007 2

The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson's disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postura ...[more]

PMID: 20002202

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Project description:Gastrointestinal (GI) disturbances are one of the earliest symptoms affecting most patients with Parkinson's disease (PD). In many cases, these symptoms are observed years before motor impairments become apparent. Hence, the molecular and cellular underpinnings that contribute to this early GI dysfunction in PD have actively been explored using a relevant animal model. The MitoPark model is a chronic, progressive mouse model recapitulating several key pathophysiological aspects of PD. However, GI dysfunction and gut microbiome changes have not been categorized in this model. Herein, we show that decreased GI motility was one of the first non-motor symptoms to develop, evident as early as 8 weeks with significantly different transit times from 12 weeks onwards. These symptoms were observed well before motor symptoms developed, thereby paralleling PD progression in humans. At age 24 weeks, we observed increased colon transit time and reduced fecal water content, indicative of constipation. Intestinal inflammation was evidenced with increased expression of iNOS and TNF? in the small and large intestine. Specifically, iNOS was observed mainly in the enteric plexi, indicating enteric glial cell activation. A pronounced loss of tyrosine hydroxylase-positive neurons occurred at 24 weeks both in the mid-brain region as well as the gut, leading to a corresponding decrease in dopamine (DA) production. We also observed decreased DARPP-32 expression in the colon, validating the loss of DAergic neurons in the gut. However, the total number of enteric neurons did not significantly differ between the two groups. Metabolomic gas chromatography-mass spectrometry analysis of fecal samples showed increased sterol, glycerol, and tocopherol production in MitoPark mice compared to age-matched littermate controls at 20 weeks of age while 16?s microbiome sequencing showed a transient temporal increase in the genus Prevotella. Altogether, the data shed more light on the role of the gut dopaminergic system in maintaining intestinal health. Importantly, this model recapitulates the chronology and development of GI dysfunction along with other non-motor symptoms and can become an attractive translational animal model for pre-clinical assessment of the efficacy of new anti-Parkinsonian drugs that can alleviate GI dysfunction in PD.

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MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.

Publications

MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease.

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