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

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  1. Very nice study even though the result is somewhat predictable. However, given the previous study showing aggregates after over-expression of just wild type synuclein, this study is an important contribution.

  2. As is often the case with transgenic rodent models of human neurodegenerative diseases, a single strain of genetically engineered animals rarely recapitulates the entire pathological spectrum associated with the human phenotype. The same is true for the intriguing A53T mouse model of familial Parkinson disease reported by Giasson et al.

    The authors present a model of mutant human a-synuclein-induced neuropathology that compares well with the CNS-wide effects of the inherited human disorder through its key abnormality, namely axonal pathology caused by accumulation of mutant α-synuclein.

    Such abnormalities were recently reported in detail by the same team on a single case from a patient with a heterozygous A53T mutation of α-synuclein (Duda et al., Acta Neuropathologica, 2002). Surprisingly, and in contrast to other rodent and fly models overexpressing human α-synuclein, mice transgenic for the wild-type version of α-synuclein appear clinically and neuropathologically unharmed. Giasson et al. demonstrate intriguing immunological, relevant biochemical, as well as histological and ultrastructural parallels between human α-synuclein-related PD and their A53T mice.

    The observed differences between these mice and A53T-linked familial Parkinsonism cases are that in the Giasson model,

    • dopaminergic neurons of the Substantia nigra are essentially spared (these are the most vulnerable brainstem nucleus in sporadic PD),
    • despite axonal pathology, actual cell loss does not appear to be a prominent feature at the age the animals were sacrificed,
    • its clinical phenotype is probably caused more by weakness related to spinal cord dysfunction and loss of postural reflexes rather than a basal ganglia-related movement disorder
    • ubiquitination of the observed α-synuclein-inclusion does not seem to be a common feature.

    To the interested researcher and clinical neurologist alike, both this pathology-rich mouse model of A53T human α-synuclein-linked Parkinsonism, as well as a recently published mouse model for the related human condition multiple systems atrophy (Kahle et al., 2002) are welcome news. These two models, in addition to others before them, reproduce neuropathological aspects of inclusion-rich diseases of the brain. It remains to be seen whether inclusion models will also help elucidate the precise mechanisms of neuronal death. Research in Huntington disease has focused our attention away from inclusions to transcriptional dysregulation by the mutant protein, as pointed out elegantly last week by Krainc and colleagues (see ARF news story).

    References:

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

    View all comments by Michael Schlossmacher
  3. "The identification of extended families showing mutations in α-synuclein and concomitant neurodegeneration resembling Parkinson's disease focused attention on the putative role of α-synuclein in Parkinson's. The discovery that α-synuclein was abundant in Lewy bodies further enhanced interest in this protein. Subsequent studies showed that the disease-related mutations in α-synuclein all increase its tendency to aggregate, suggesting that α-synuclein might be directly connected with Lewy body formation. This has raised hopes that expressing the mutant forms of human α-synuclein in mice might yield models for Parkinson's or other synucleinopathies.

    The has not been straightforward, though. Many of the initial transgenic mice over-expressing α-synuclein did not produce pathology. The first success came with Eliezer Masliah's mouse that mildly overexpresses wild-type human α-synuclein (see ARF news story). It showed dopaminergic deficits and some inclusions but did not show extensive cell death, and the inclusions had only a limited resemblance to Lewy bodies. Having a model, however, is extremely valuable, and Masliah and colleagues have used it to demonstrate that Aβ increases α-synuclein aggregation (see ARF news story), and that β-synuclein inhibits α-synuclein aggregation (see ARF news story).

    Other mice expressing A30P α-synuclein develop age-dependent accumulation of α-synuclein, but no significant clinical phenotypes at 1 year of age (Kahle et al., 2000). Van der Putten and colleagues produced an A53T α-synuclein mouse, which did develop both axonal degeneration and motor disfunction by 1 year of age, but no fibrillar pathology and no cell death (van der Putten et al., 2000). The lowly fruit fly has proven to be the stand-out in the α-synuclein world, because transgenic Drosophila expressing A53T α-synuclein develop inclusions resembling Lewy bodies and dopaminergic degeneration (Auluck et al., 2002; see ARF news story). However, no differences were observed between wild-type and mutant α-synuclein.

    The present paper by Giasson and colleagues, is particularly interesting because the model recapitulates aspects of synucleinopathies that have been absent in other models. The authors generated mice expressing wild type or A53T α-synuclein driven by a PrP promoter. The A53T mice develop intracytoplasmic fibrillar inclusions, severe motor impairment, and neurodegeneration. The fibrillar inclusions are striking because they have a diameter of 10-16 nm, similar to that observed in human tissue. The wild-type mice, in contrast, do not develop disease. Yet the model is still not perfect. No pathology occurred in the tyrosine hydroxylase-positive neurons of the substantia nigra, and little cell death was observed. This means that the flies remain the only animal model in which pathology is strongly associated with dopaminergic neurons.

    The important advance for the field here comes from the availability of a mouse that has fibrillar pathology reminiscent of human pathology, and sensitivity to mutations as seen in humans. This model will enable more detailed studies of the physiology of α-synuclein pathology, including studies of the regulators of aggregation, inhibitors of aggregation, and the mechanism by which aggregates are toxic. The authors speculate that the PrP promotor is the reason why pathology in these mice parallels human pathology better than in other mice, which have used a Thy1 or PDGF promoter. This remains to be determined. The expression patterns of the different promoters do very greatly. While there is some overlap in expression patterns, generally Thy1 and PDGF drive expression most in the cortex and hippocampus, while PrP drives expression most in the brain stem and spinal cord. Maximizing expression in neurons that are prone to developing inclusions might be key.

    The mechanisms underlying the anatomic specificity of aggregate formation is one of the unsolved mysteries in neurodegenerative research. Many proteins aggregate in multiple different cell types in the laboratory but, in vivo, aggregation occurs with striking anatomical specificity. Clearly, we have much to learn before we understand the factors that regulate α-synuclein aggregation and neurodegeneration. Regardless of the reasons for development of fibrillar pathology, these results provide support for the role of α-synuclein in the pathophysiology of Parkinson's disease and other synucleinopathies".

    References:

    . Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J Neurosci. 2000 Sep 1;20(17):6365-73. PubMed.

    . Neuropathology in mice expressing human alpha-synuclein. J Neurosci. 2000 Aug 15;20(16):6021-9. PubMed.

    . Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science. 2002 Feb 1;295(5556):865-8. PubMed.

    View all comments by Benjamin Wolozin