A53T alpha-synuclein mice

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

Two groups, about a month apart in 2002. Benoit Giasson, John Trojanowski, Virginia Lee and colleagues at the University of Pennsylvania (Neuron, May); and Michael Lee, Don Price, Ted Dawson and colleagues at Johns Hopkins (PNAS, June). Funders were not checked.

What happened

Both teams put human alpha-synuclein into mice. Both used the mouse prion-protein (PrP) promoter, a gene "on-switch" that Alzforum says drives expression mainly in the brainstem and spinal cord (for Lee's mice the promoter is stated in the paper). The A53T mutation is the one found in the families of landmark 4. Mice carrying normal human synuclein stayed well. The A53T mice developed progressive, severe movement impairment ending in paralysis and death. Giasson's mice had fibril-filled inclusions inside neurons, with fibrils 10–16 nm wide, like those in human tissue. Lee's team also tested the A30P mutation, and only A53T made the animals ill. Neither team reported loss of dopamine neurons in the substantia nigra. Lee's paper says striatal dopamine was not significantly lost and that nigral dopamine neurons "are free of obvious neuropathological changes" (data not shown); it suggests rodent neurons may resist synuclein toxicity better than human ones.

Correction to the candidate list: the 2002 papers were not the first synuclein mice, nor the first A53T mice. Masliah et al. (Science, February 2000) made mice with normal human synuclein that formed inclusions and lost dopamine nerve endings. Van der Putten et al. (Novartis, J Neurosci, August 2000) put A53T synuclein under the Thy1 promoter and reported neuronal degeneration and motor defects, though the gene was not switched on in nigral dopamine neurons. Integrity note: the 2000 Science paper appears on the PubPeer-linked list of Masliah papers kept by Alzforum, but I found no correction, expression of concern or retraction for it (checked 19 Oct 2026); the 2002 A53T lines and the Novartis mice were made by other labs and do not depend on it. What the 2002 lines added was a reproducible, fatal paralysis with fibrillar inclusions that depended on the A53T change.

Why it moved us toward a cure

It showed in a whole animal that mutant synuclein by itself, with no toxin, can cause aggregation and neuron damage. That backs the genetic argument of landmarks 4, 5 and 14 and gave a test-bed for studying how clumps form and for trying drugs that block aggregation. Its main limit is the missing nigral cell loss, so it models synuclein toxicity better than it models Parkinson's itself.

Outcome

Advanced. A53T synuclein mouse strains remain in use, for example as hosts for injected synuclein fibrils (Byrne et al., Sci Rep 2025), though that paper does not say which original line it used. Their limit is the missing nigral cell loss.

Sources

• Giasson et al., Neuron 2002;34(4):521–533, DOI 10.1016/s0896-6273(02)00682-7 (record page)
• Lee et al., PNAS 2002;99(13):8968–8973, DOI 10.1073/pnas.132197599
• Alzforum on the models: Giasson mouse, with commentary · model record · Lee mouse
• Masliah et al., Science 2000;287:1265–1269, DOI 10.1126/science.287.5456.1265, PMID 10678833 (Alzforum on it) · Alzforum list of Masliah papers with PubPeer links and corrections
• Van der Putten et al., J Neurosci 2000;20:6021–6029, DOI 10.1523/JNEUROSCI.20-16-06021.2000, PMID 10934251
• Giasson et al., PMID 12062037 (abstract, authors, Penn affiliation) · Byrne et al., Sci Rep 2025;15:26537, DOI 10.1038/s41598-025-10705-8
• Not yet verified: the full text of Giasson et al. (publisher page blocked; the nigral result for those mice rests on Alzforum's commentary); funders; whether Masliah's was the very first synuclein mouse; which drugs have been tested in the A53T lines.