Abstract
Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson's disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson's disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.
Highlights
Martin Ingelsson *Additional proof of concept studies have demonstrated the feasibility of using antibodies that can selectively measure particular disease-related oligomeric species (Sierks et al, 2011; Brannstrom et al, 2014; Unterberger et al, 2014), but no larger case-control studies based on such antibodies have so far been reported
Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
Widespread neuronal loss can be seen in the brain stem and neocortex of patients with Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and the Lewy body variant of Alzheimer’s disease (LBAD)
Summary
Additional proof of concept studies have demonstrated the feasibility of using antibodies that can selectively measure particular disease-related oligomeric species (Sierks et al, 2011; Brannstrom et al, 2014; Unterberger et al, 2014), but no larger case-control studies based on such antibodies have so far been reported In addition to these direct clinical and clinico-pathological observations, a large number of studies have investigated the physiological effects of α-synuclein oligomers on various cellular, tissue and animal models. The direct link between oxidative stress and αsynuclein aggregation is unknown, short-lived reactive oxygen species, known to initiate lipid peroxidation of polyunsaturated fatty acids, have been shown to be present in neuronal cell membranes Such peroxidation can lead to the formation of reactive aldehydes which, in addition to being cytotoxic themselves, can bind covalently both to α-synuclein and to other proteins and thereby alter their normal structure and function (Esterbauer et al, 1991).
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