E46K Human α-Synuclein Transgenic Mice Develop Lewy-like and Tau Pathology Associated with Age-dependent, Detrimental Motor Impairment

Synucleinopathies are a group of neurodegenerative disorders associated with the formation of aberrant amyloid inclusions composed of the normally soluble presynaptic protein alpha-synuclein (alpha-syn). Parkinson disease is the most well known of these disorders because it bears alpha-syn pathological inclusions known as Lewy bodies (LBs). Mutations in the gene for alpha-syn, including the E46K missense mutation, are sufficient to cause Parkinson disease as well as other synucleinopathies like dementia with LBs. Herein, we describe transgenic mice expressing E46K human alpha-syn in CNS neurons that develop detrimental age-dependent motor impairments. These animals accumulate age-dependent intracytoplasmic neuronal alpha-syn inclusions that parallel disease and recapitulate the biochemical, histological, and morphological properties of LBs. Surprisingly, the morphology of alpha-syn inclusions in E46K human alpha-syn transgenic mice more closely resemble LBs than the previously described transgenic mice (line M83) that express neuronal A53T human alpha-syn. E46K human alpha-syn mice also develop abundant neuronal tau inclusions that resemble neurofibrillary tangles. Subsequent studies on the ability of E46K alpha-syn to induce tau inclusions in cellular models suggest that both direct and indirect mechanisms of protein aggregation are probably involved in the formation of the tau inclusions observed here in vivo. Re-evaluation of presymptomatic transgenic mice expressing A53T human alpha-syn reveals that the formation of alpha-syn inclusions in mice must be synchronized; however, inclusion formation is diffuse within affected areas of the neuroaxis such that there was no clustering of inclusions. Collectively, these findings provide insights in the mechanisms of formation of these aberrant proteinaceous inclusions and support the notion that alpha-syn aggregates are involved in the pathogenesis of human diseases.