The Role of Alpha-Synuclein Pathology

Abstract

Alpha-synuclein (αSyn) is a conformationally flexible protein that is known to be involved in key neuronal biological processes and the pathogenesis of Parkinson’s disease (PD). The aggregation of αSyn in the brain is not only the neuropathological hallmark of PD but also characterizes other primary synucleinopathies, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). These disorders share common clinical motor symptoms, namely, parkinsonism, which is associated with the loss of nigral dopaminergic neurons. Pathologically the selective neurodegeneration in synucleinopathies is linked to αSyn dysfunction and its abnormal interactions with other proteins. It should be noted that the aggregation of αSyn is not an absolute pathogenic cause for clinically or genetically diagnosed PD, as a minority of patients have substantial loss of nigral dopaminergic neurons in the absence of αSyn pathology. In addition, αSyn pathology is a commonly observed autopsy finding in asymptomatic senescent brains, confirming that αSyn pathology can occur independently of parkinsonism. Presently, there is no causative treatment for synucleinopathies; therefore, targeting αSyn remains the key research focus. Despite the importance of αSyn in the pathology of synucleinopathies, there is no consensus on reliable markers for defining toxic pathogenic αSyn aggregates in postmortem human brain tissue or on any critical αSyn-inducing pathological events. As such, there is an urgent need to establish a panel of antibodies and animal models for studying synucleinopathies. This chapter summarizes the traditional and recently developed methodologies in the field with suggestions on toolkits to assess the role of αSyn pathology.