Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson disease model

Parkinson Disease (PD) is characterized by the presence of alpha-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between alpha-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 alpha-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of alpha-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm alpha-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of alpha-synuclein aggregates and an increase in dispersed small alpha-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b function in vivo supporting that targeting alpha-synuclein aggregation is a promising therapeutic approach for PD.