The Role of Alpha-Synuclein Pathology

Alpha-Synuclein (aSyn) 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 aSyn 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 aSyn dysfunction and its abnormal interactions with other proteins. It should be noted that the aggregation of aSyn 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 aSyn pathology. In addition, aSyn pathology is a commonly observed autopsy finding in asymptomatic senescent brains, confirming that aSyn pathology can occur independently of parkinsonism. Currently, there is no causative treatment for synucleinopathies, therefore, targeting aSyn remains the key research focus. Despite the importance of aSyn in the pathology of synucleinopathies, there is no consensus on reliable markers for defining toxic pathogenic aSyn aggregates in post-mortem human brain tissue or on any critical aSyn-inducing pathological events. As such, there is an urgent need to establish a panel of antibodies and animal models for studying synucleinopathies. This chapter summarises the traditional and recently developed methodologies in the field with suggestions on toolkits to assess the role of aSyn pathology.