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.

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

“…In keeping with these findings, increased exposure of the mitochondrial genome to TFAM has been reported to enhance 7S DNA association and mtDNA replication in an in organello DNA synthesis system 32. In line with our hypothesis stating that TFAM deficiency induces mtDNA depletion in IPD, conditional silencing of TFAM provokes PD‐like features such as respiratory chain dysfunction, degeneration of dopaminergic SN neurons, and progressive impairment of motor function in mice 33, 34. Remarkably, in addition to its effect as a CI inhibitor, the PD‐inducing reagent 1 methyl‐4‐phenylpyridinium also interferes with mtDNA replication by destabilization of the mitochondrial D‐loop 35, 36.…”

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

“…Interestingly, the progression of the observed motor symptoms (i.e., vertical movements declining earlier and faster than the horizontal movements) followed a pattern similar to that reported in the MitoPark PD mice model (32,33). This behavioral phenotype has been suggested to model the early occurrence of axial/postural instability in PD (32). According to the locomotor measurements, the age of Lmx1a/b ablation seems to be critical.…”

Mitochondrial Dysfunction in Neurodegenerative Diseases

“…It stabilizes mtDNA, regulates mtDNA copy number in vivo, and is essential for mitochondrial biogenesis (Larsson et al, 1998). The MitoPark mice survive to adulthood and then slowly develop a Parkinsonian phenotype (Ekstrand et al, 2007;Galter et al, 2010). Furthermore, cellular changes similar to those seen in idiopathic PD are observed, such as intracellular inclusions in DA neurons, degeneration of DA pathways, and loss of striatal dopamine.…”