Acta Neuropathologica

, Volume 115, Issue 1, pp 87–95

α-Synucleinopathy models and human neuropathology: similarities and differences

Authors

    • Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie-Institute for Clinical Brain ResearchUniversity Clinics Tübingen
Review

DOI: 10.1007/s00401-007-0302-x

Cite this article as:
Kahle, P.J. Acta Neuropathol (2008) 115: 87. doi:10.1007/s00401-007-0302-x

Abstract

Point mutations and genomic multiplications in the α-synuclein (αSYN) gene cause autosomal-dominant Parkinson’s disease. Moreover, αSYN fibrils are the major component of Lewy bodies, the neuropathological hallmarks of Parkinson’s disease and dementia with Lewy bodies as well as of glial cytoplasmic inclusions in multiple system atrophy. These diseases are collectively referred to as α-synucleinopathies. Cellular mechanisms regulating αSYN fibril formation and toxicity are intensely studied in vitro, and in cell culture and diverse animal models. Specific neuropathology was achieved in transgenic mouse models using several promoters to express human wild-type and mutant αSYN in brain regions affected by the various α-synucleinopathies. Somatodendritic accumulation of the transgenic αSYN with neuritic distortions was a common finding. The nigrostriatal dopaminergic projections were surprisingly resistant to α-synucleinopathy in transgenic mice, although they tended to be more vulnerable to neurotoxins. In a few mouse models, αSYN aggregated in an age-dependent manner into genuine fibrillar amyloid. Brain region selective αSYN neuropathology correlated with specific behavioral impairments, such as locomotor dysfunction and cognitive decline. Thus, the αSYN fibrillization process is tightly linked to neuropathology. The role and thus therapeutic potential of post-translational modifications (ubiquitinylation, oxidation, phosphorylation, truncation) and modifier genes on αSYN neuropathology can now be assessed in valid transgenic mouse models of α-synucleinopathies.

Keywords

SynucleinTransgenic miceParkinson’s diseaseDementia with Lewy bodiesMultiple system atrophy

Copyright information

© Springer-Verlag 2007