Human-based studies on α-synuclein deposition and relationship to Parkinson's disease symptoms

This article reviews the current knowledge on α-synuclein and its cellular locations in studies using human brain tissue. Alterations in the conformation and distribution of α-synuclein are examined in Parkinson's disease and the relationship between clinical symptoms and pathology explored. α-Synuclein as a molecular chaperone has several isoforms and is known to have different environment-dependent conformations. Processing methods for studying human brain tissue significantly impact on the conformational type of α-synuclein analysed, and antibody species used for the in situ detection of α-synuclein give variable results depending on the epitope visualised. Human studies show that α-synuclein is not isolated to neurons, but is also found in glia, making the interpretation of studies using brain tissue homogenates less clearly related to neurons. These methodological issues impact significantly on our understanding of the form, location, and therefore function of α-synuclein in normal human brain tissue. There are less methodological issues regarding highly aggregated α-synuclein found in the major hallmark of Parkinson's disease, the Lewy body. However, it remains unclear whether these α-synuclein inclusions are harmful to host neurons or provide protection. Several correlations exist between the clinical symptoms of Parkinson's disease and the distribution of Lewy pathology, the strongest being the association between limbic and cortical Lewy bodies and well-formed visual hallucinations. Further correlation studies in prospectively-followed patients and, perhaps more importantly, controls are required in order to determine normal versus pathologic α-synuclein and how to detect such differences in clinical situations.