Axonopathy in an α-Synuclein Transgenic Model of Lewy Body Disease Is Associated with Extensive Accumulation of C-Terminal Truncated α-Synuclein

Progressive accumulation of alpha-synuclein (alpha-syn) in Limbic and striatonigral systems is associated with the neurodegenerative processes in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). The mutine Thy-1 (mThy1)-alpha-syn transgenic (tg) model recapitulates aspects of degenerative processes associated with a-syn accumulation in these disorders. Given that axonal and synaptic pathologies are important features of DLB and PD, we sought to investigate the extent and characteristics of these alterations in mThy1-alpha-syn tg mice and to determine the contribution of alpha-syn c-terminally cleaved at amino acid 122 (CT alpha-syn) to these abnormalities. We generated a novel polyclonal antibody (SYN105) against the c-terminally truncated sequence (amino acids 121 to 123) of alpha-syn (CT alpha-syn) and performed immunocytochemical and ultrastructural analyses in mThy1-alpha-syn tg mice. We found abundant clusters of dystrophic neurites in Layers 2 to 3 of the neocortex, the stratum Lacunosum, the dentate gyrus, and cornu ammonis 3 of the hippocampus, striatum, thalamus, midbrain, and pons. Dystrophic neurites displayed intense immunoreactivity detected with the SYN105 antibody. Double-labeling studies with antibodies to phosphorylated neurofilaments confirmed the axonal Location of full-Length and CT alpha-syn. alpha-Syn immunoreactive dystrophic neurites contained numerous electrodense laminated structures. These results show that neuritic dystrophy is a prominent pathologic feature of the mThy1-alpha-syn tg model and suggest that CT alpha-syn might play an important role in the process of axonal damage in these mice as well as in DLB and PD. (Am J Pathol 2013, 182: 940-953; http://dx.doi.org/10.1016/j.ajpath.2012.11.018)