Abstract
Alpha-synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic αsyn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different αsyn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic αsyn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic αsyn from peripheral organs to the brain.
Highlights
DANDRITE-Danish Research Institute of Translational Neuroscience, Department of Biomedicine, Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus, Denmark
Parkinson’s disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF) and multiple system atrophy (MSA) are classified as synucleinopathies, called α-synucleinopathies, as they all are characterized by pathological accumulation of the protein αsyn
Patients are classified as PD, DLB, PAF or MSA based on their clinical symptoms and later, post-mortem by the spatiotemporal distribution of pathogenic αsyn [8]
Summary
The hypothesized gut-to-brain spread of αsyn in PD (and other synucleinopathies) is still heavily debated, since several autopsy studies could not confirm the proposed caudorostral spread and showed that αsyn pathology in the CNS is quite often present without the occurrence of αsyn in the ENS, vagus nerve or dorsal motor nucleus of the vagus nerve [87,88]. The brain-first type is hypothesized to be associated with a limbic/amygdala-predominant pathology pattern in the brain, and is characterized by an RBD-negative prodromal phase and nigrostriatal dopamine deficit prior to autonomic dysfunction. Both disease subtypes converge to a homogeneous advanced disease stage over time where the entire brain and several peripheral organs are affected. These data support that body-first PD is characterized by more symmetric distribution, most likely due to more symmetric propagation of pathogenic αsyn within the brain, compared to brain-first PD [95]. Brain-first PD is more heterogeneous compared to body-first PD [96]
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