Human -synuclein-harboring familial Parkinson’s disease-linked Ala-53 3 Thr mutation causes neurodegenerative disease with -synuclein aggregation in transgenic mice

Mutations in -synuclein ( -Syn) cause Parkinson’s disease (PD) in a small number of pedigrees with familial PD. Moreover, -Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of -Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 3 Pro (A30P) or Ala-53 3 Thr (A53T) human -Syns. The mice expressing the A53T human -Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of -Syn and ubiquitin. Consistent with abnormal neuronal accumulation of -Syn, brain regions with pathology exhibit increases in detergent-insoluble -Syn and -Syn aggregates. Our results demonstrate that the A53T mutant -Syn causes significantly greater in vivo neurotoxicity as compared with other -Syn variants. Further, -Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble -Syn.