A new mouse model of Parkinson's published in the current early online edition of PNAS develops a particularly severe motor disorder similar to Parkinson's disease but, as with a similar model reported last month, no degeneration of substantia nigra neurons (see related news item).

Michael Lee and colleagues at Johns Hopkins University in Baltimore, Maryland, and at the National Cancer Institute in Frederick, Maryland, created a mouse carrying the human gene encoding a mutation in α-synuclein, as done by Giasson and colleagues. The A53T mutation causes a familial form of PD. As with the previous report, this mouse develops insoluble aggregates containing α-synuclein that are reminiscent of the Lewy bodies of PD and other α-synucleinopathies, such as dementia with Lewy bodies and multiple systems atrophy. There was also glial evidence of neurodegeneration in motor areas of the brain, which was manifested in a progressive motor disorder that lead to early death.

Yet both these models fail to reproduce loss of dopamine neurons in the substantia nigra, the hallmark of PD. Lee and colleagues suggests that rodent SN neurons may be more resistant to α-synuclein-induced neurodegeneration, an idea that has support from in vitro and other transgenic studies.—Hakon Heimer


  1. This paper adds to an increasing number of transgenic mice over-expressing α-synuclein that show age-dependent pathology. The mouse generated by Mike Lee and colleagues shows progressive loss of motor function and premature death. This observation is similar to that observed by Kahle et al., 2001, and by Giasson et al. , 2002, see previous comments. Lee observed that only mice expressing the A53T a-synuclein exhibit the loss of motor function; in this regard his mouse is similar to that of Giasson, and different from that of Kahle, which used an A30P-α-synuclein construct. Both Giasson and Lee used the PrP promoter, while Kahle et al. used the Thy1 promoter. Thus, the Giasson and Lee mice have a mutation sensitivity that most closely resembles the human phenotype.

    A critical question in evaluating these mice is to examine the type of pathology that develops. The Lee mouse develops insoluble synuclein, which appears to be common to most of the transgenic mice over-expressing α-synuclein. This includes another mouse recently published by Kahle et al., which expresses α-synuclein in oligodendrocytes. However, the only mouse that develops filaments resembling those in Parkinson’s disease or other synucleinopathies is the Giasson et al. strain. This key issue was either not examined, or examined and not reported, by Lee and colleagues.

    It is surprising that none of these transgenic α-synuclein models show degeneration of dopaminergic neurons of the substantia nigra, although the mouse developed by Masliah et al. shows some dopaminergic dysfunction. Instead, degeneration was observed in areas such as the cerebellum (Lee mouse) and spinal cord/brain stem (Giasson and Kahle mice), this despite the presence of α-synuclein transgene expression in the substantia nigra, which Lee et al. specifically examined. The reason for this disparity between the human and mouse phenotype is unclear, but it raises the possibility that α-synuclein aggregation alone does not account for the distribution of pathology and degeneration in Parkinson’s disease. These results stand in contrast to Greenamyre’s finding that rotenone treatment causes dopaminergic degeneration (Betarbet et al., 2000). It seems likely that a variety of environmental and genetic factors work together to elicit the pathophysiology of Parkinson’s disease.


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  2. This paper rigorously demonstrates that overexpression of one mutant form of alpha-synuclein results in synuclein aggregation, inclusions, and neurological disease while overexpression of wild-type human synuclein and another mutant does not. These mice should be very useful for further studying the pathophysiology of alpha-synucleinopathies.

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News Citations

  1. Presenting: A Not-Quite-Parkinson's Mouse Model

Further Reading

Primary Papers

  1. . Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73. PubMed.