Take a deep breath. Mitochondrial respiration problems could be central to Parkinson disease (PD) pathology. That’s according to Nils-Göran Larsson and colleagues at the Karolinska Institute, Stockholm, Sweden. In this week’s PNAS online, the researchers describe how mitochondrial deficiency in midbrain dopaminergic neurons mimics this devastating disease in mice rather faithfully, with late-onset and slowly progressing neurological symptoms. The results suggest that damage to mitochondria is sufficient to cause Parkinson’s-like neurodegeneration.
Mitochondria are the cell’s generators, pumping out heat and the high-energy compounds that drive power-hungry processes such as muscle contraction, protein synthesis, and neurotransmitter release—neurons are laden with the tiny organelles. This is not the first time mitochondria have been linked to neurodegenerative diseases. Toxic reactive oxygen species generated by the mitochondrial respiratory chain and mutations in mitochondrial DNA (mtDNA) are both suspects in Parkinson disease pathology (see ARF related news story). Yet it has been difficult to determine with certainty if mitochondrial damage is the cause or merely an effect of PD. Even in the case of MPTP, a mitochondrial toxin responsible for some rare cases of Parkinson’s, it is unclear if the disease directly results from damage to mitochondria in midbrain dopaminergic (DA) neurons that are primarily affected by the disease, or whether other MPTP toxicities or damage to other areas of the brain play a role. The strength of this new study is that it specifically probes the role of those DA neurons.
Larsson and colleagues took advantage of the widely used Cre-lox recombination system that selectively removes pieces of DNA from the genome. First author Mats Ekstrand and colleagues trained the system on the gene for mitochondrial transcription factor A (Tfam). Tfam is essential for healthy mitochondria because it not only controls the amount of DNA made in each organelle, but, as a master transcription factor, it also controls expression of mitochondrial genes. The mitochondrial genome encodes 13 key subunits of the respiratory chain (most other mitochondrial genes are actually encoded in the nucleus), and therefore loss of Tfam might be expected to have serious consequences for oxidative respiration. And that’s just what Ekstrand and colleagues found.
The scientists crossed mice expressing Cre recombinase under the control of the dopamine transporter gene with mice expressing Lox-flanked Tfam alleles. The resulting MitoPark mouse strain has a homozygous disruption of Tfam in midbrain DA neurons and an unhealthy loss of cytochrome c oxidase (Cox) to boot. Cox catalyzes the very last of the respiratory chain reactions, and without it the complete pathway slows to a crawl.
What are the physiological consequences of slowing down respiration in these mitochondria? Young mice appeared to cope just fine; however, by 14-15 weeks they began to tremble, twitch, and their limbs became rigid—all tell-tale signs of parkinsonism. After a single dose of L-dopa, the treatment of choice for people with Parkinson’s, the mice improved considerably. However, much like in human cases, the drug proved less and less effective as the animals aged.
The symptoms can be explained by a gradual loss of DA neurons in the dorsolateral striatum beginning around week 12. This was more apparent in the substantia nigra, the area most badly affected in Parkinson’s patients. Even earlier, at about 6 weeks, the researchers detected the accumulation of cytoplasmic aggregates. These did not contain α-synuclein, a major component of the Lewy bodies found in the neurons of people with PD. The exact nature of the aggregates is unclear, but the fact that a double membrane reminiscent of the mitochondrial membrane surrounded some of them suggests that they may represent mitochondrial degradation products. Indeed, the authors speculate that “…reduced mtDNA expression may lead to an aggregation of nucleus-encoded proteins in the mitochondria of DA neurons, and that that event could initiate an aggregation process also involving non-mitochondrial proteins.”
The similarities between this new mouse phenotype and Parkinson’s pathology suggest that the disease may, at least in some cases, start in the mitochondria. Whether this means reactive oxygen species play a role is unclear. The MitoPark mouse may help answer this vexing question about the disease.—Tom Fagan