Abstract
BackgroundMisfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE® immunotherapy approach, either alone or in combination with Anle138b, in a PLP-α-syn mouse model.MethodsThe PLP-α-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and α-synuclein pathology.ResultsThe PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03.ConclusionsPD03 and Anle138b can selectively target oligomeric α-synuclein, resulting in attenuation of neurodegeneration in the PLP-α-syn mice. Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.
Highlights
Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta
PD03 is immunogenic and ameliorates motor symptoms and nigral degeneration in proteolipid protein (PLP)-α-syn mice In study I, PLP-α-syn mice were treated with PD03 conjugated to keyhole limpet hemocyanin (KLH) as the carrier to target α-syn pathology in multiple system atrophy (MSA) mice
Two out of 12 transgenic mice died in the vehicle-treated PLP-α-syn group, while no death occurred in the PD03-treated PLP-α-syn mice and the healthy control group
Summary
Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. The PLP-α-syn transgenic mouse is a model of αsynucleinopathy that overexpresses human α-syn under the proteolipid protein (PLP) promoter in oligodendrocytes [13]. It recapitulates the glial cytoplasmic inclusion (GCI)-like pathology, as well as the selective neuronal loss and motor impairment [8, 13,14,15], replicating the Parkinson form of MSA (MSA-P). The oligomeric species of α-syn have been detected in the brains of PLP-αsyn mice at the time of initial microglial activation and neuronal loss in the substantia nigra pars compacta (SNc), supporting their role in the progression of the disease phenotype [8]. The molecular tweezer CLR01 successfully rescued nigral dopaminergic neurons in the PLP-α-syn model by reducing the level of high-molecular species of α-syn in the brain [17]
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