. 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.


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  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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    . Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron. 2002 May 16;34(4):521-33. PubMed.

    . Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 2002 Jun;3(6):583-8. PubMed.

    . Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol. 2001 Dec;159(6):2215-25. PubMed.

    . Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 2000 Feb 18;287(5456):1265-9. PubMed.

    View all comments by Benjamin Wolozin
  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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