alpha-Synucleinopathy models and human neuropathology: similarities and differences.
Point mutations and genomic multiplications in the alpha-synuclein (alphaSYN) gene cause autosomal-dominant Parkinson's disease. Moreover, alphaSYN 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 alpha-synucleinopathies. Cellular mechanisms regulating alphaSYN 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 alphaSYN in brain regions affected by the various alpha-synucleinopathies. Somatodendritic accumulation of the transgenic alphaSYN with neuritic distortions was a common finding. The nigrostriatal dopaminergic projections were surprisingly resistant to alpha-synucleinopathy in transgenic mice, although they tended to be more vulnerable to neurotoxins. In a few mouse models, alphaSYN aggregated in an age-dependent manner into genuine fibrillar amyloid. Brain region selective alphaSYN neuropathology correlated with specific behavioral impairments, such as locomotor dysfunction and cognitive decline. Thus, the alphaSYN 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 alphaSYN neuropathology can now be assessed in valid transgenic mouse models of alpha-synucleinopathies.
Kahle
Philipp J
PJ
Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University Clinics Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany. Philipp.Kahle@Uni-Tuebingen.de
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D051844:alpha-Synuclein