Abstract
Parkinson’s disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1–120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-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. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20–500 nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.
Highlights
Materials and methodsParkinson’s disease (PD) and other α-synucleinopathies are characterized by aggregation of α-synuclein in Lewy bodies (LBs), Lewy neurites (LNs) and glial cytoplasmic inclusions [17, 32, 33]
Immunoblotting revealed the presence of the transgenic protein in brain regions and neurons with TH-expression, such as substantia nigra (SN), striatum and olfactory bulb (OB), while no transgenic protein was expressed in cortex or cerebellum, where TH expression is not prominent (Fig. 1b)
The distribution of 1–120 hαSyn followed the TH expression pattern, staining being evident in substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) neurons, while no staining was evident in the SN pars reticulata, where αSyn is instead found in wt C57Bl/6J mice (Fig. 1d)
Summary
Materials and methodsParkinson’s disease (PD) and other α-synucleinopathies are characterized by aggregation of α-synuclein (αSyn) in Lewy bodies (LBs), Lewy neurites (LNs) and glial cytoplasmic inclusions [17, 32, 33]. It is widely accepted that the process of αSyn aggregation in PD is directly involved in the pathogenesis and progression of the disease, and motor symptoms are mainly related to the dysfunction of the nigrostriatal dopamine (DA) system. Availability of an animal model of PD that reproduces progressive DA dysfunction and DA neuronal death with progressive αSyn aggregation in the nigrostriatal system is crucial for understanding disease mechanisms and the testing of novel therapies for treating movement deficit. Until recently it was difficult to study quantitatively the early steps of αSyn aggregation and the effects of aggregate inhibitors in a living system, mainly due to the limitations in the diffraction of conventional microscopy. With the use of super resolution microscopy like STORM, dSTORM, STED and aptamer DNA PAINT [30] and advanced analysis algorithms [3], it is possible to identify changes in αSyn aggregation at the single molecule level in in vivo systems and understand the mechanistic nature of aggregate inhibitors
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