MitoPark mouse

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Mats Ekstrand, Nils-Göran Larsson, Lars Olson and colleagues at the Karolinska Institute, Stockholm. Support came from Swedish funders (including the Parkinson Foundation in Sweden and the Swedish Research Council), the US NIH and the Michael J. Fox Foundation. Three authors, including Larsson and Olson, co-own a company that holds commercial rights to the mice.

What happened

Mitochondria are the cell's power plants, with their own small genome. The team deleted Tfam, a gene needed to maintain and read that genome, only in dopamine neurons, using the Cre-lox method (a genetic scissors-and-switch system) driven by the dopamine transporter gene. The mice, nicknamed MitoPark, looked normal when young. Inclusions (clumps of protein and membrane) were present in dopamine neurons at 6 weeks, loss of dopamine nerve endings in the striatum began at about 12 weeks, and reduced movement and exploration first showed at 14–15 weeks. Tremor, twitching and stiff limbs appeared around 20 weeks. A single dose of levodopa markedly improved movement, with a response that ended abruptly in older mice, which the authors likened to "wearing off" in patients. Loss was greater and earlier in the substantia nigra than in the neighbouring ventral tegmental area. PNAS 104:1325–1330, January 2007.

Why it moved us toward a cure

Human evidence for mitochondrial failure (landmark 11) was only correlation. MitoPark showed that energy-machinery failure confined to dopamine neurons is enough to produce slowly progressive parkinsonism with the right cell loss pattern. It gave a slow model for testing neuroprotective drugs, and it suits the genetic mitochondrial-quality-control story of landmark 15.

Outcome

Open. The model is still in use: 2024–26 papers test a GLP-1 drug (PT320, a slow-release exenatide) and nose-to-brain nanoparticles in MitoPark mice, for example Wang 2024. All are mouse results; none has been shown to help patients. Limits: the authors report that the inclusions did not contain alpha-synuclein, so they are not Lewy bodies; commentators told Alzforum that the later loss in the ventral tegmental area differs from the human pattern and that the model cannot show whether mitochondrial damage is the cause in people. No correction or retraction was found (Europe PMC, Crossref).

Sources

• Ekstrand et al., PNAS 2007;104:1325–1330, DOI 10.1073/pnas.0605208103 (PMC1783140)
• Alzforum, "New Mouse Model Links Mitochondria to Parkinson Disease"
• Wang et al., J Biomed Sci 2024;31:38, DOI 10.1186/s12929-024-01025-6 (PT320 delays dopamine degeneration in MitoPark mice)
• Not yet verified: how many drug studies in MitoPark have been reproduced.