Abstract

α-Synuclein, β-synuclein, and γ-synuclein range from 127 to 140 amino acids in length, and are 55%–62% identical in sequence with a similar domain organization. They are encoded by three genes located on chromosomes 4q23 ( SNCA ), 5q35 ( SNCB ), and 10q21 ( SNCC ). By immunohistochemistry, α- and β-synucleins are abundant and concentrated in nerve terminals, with little staining of cell bodies and dendrites. Ultrastructurally, they are found in close proximity to synaptic vesicles. In contrast, γ-synuclein is present throughout the nerve cells in many brain regions. For a long time, synucleins were believed to have little ordered structure. However, recent work has shown that native α-synuclein is a homotetramer with a predominantly α-helical conformation. Synucleins are only identified in ver­tebrates. A neurodegenerative pathway leading from soluble to insoluble, filamentous tau is central to the neurodegenerative process in the human tauopathies. The availability of animal models exhibiting the essential molecular and cellular fea­tures of the human diseases has opened the way to a detailed understanding of the neurodegenerative process and the iden­tification of genetic and pharmacological modifiers. Besides hyperphosphorylation and aggregation, clearance of tau, immunotherapy, cell replacement, and microtubule stabilization are being pursued as potential therapies.

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