Accumulation of alpha-synuclein is a pathological feature in several neurological diseases. Its characterization has allowed for a re-grouping of diseases according to the expected pathology. The clinical syndrome of PD can now be classified into forms with and without alpha-synuclein pathology. DLB and PDD are synucleinopathies, and MSA shows alpha-synuclein pathology with glial inclusions. ADHD symptoms commonly occur in persons that will subsequently develop DLB. A similar phenomenon may be the early personality changes and frontotemporal atrophy in patients with SNCA multiplication. RLS is not known to have alpha-synuclein pathology, but as PD and ADHD, involves a hypodopaminergic state. Furthermore, PD and RLS co-occur in families in a way that suggests common inheritance. A proportion of patients with ET have brainstem Lewy body pathology. Gaucher disease and other lysosomal storage disorders also have alpha-synuclein pathology. Alpha-synuclein is a naturally unfolded protein. Non-fibrillar oligomeres may be the toxic species, and Lewy body formation may in fact be protective. Inhibiting alpha-synuclein toxicity seems to be an attractive novel treatment strategy and several approaches are being developed. When such treatments become available, clinicians will need to be familiar with the clinical features that distinguish the synucleinopathies from their look-alikes.
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