PET imaging of α-synuclein
α-synuclein (α-syn) is a small protein (140 amino acids) which is highly conserved in vertebrates and is abundant in the brain, especially in presynaptic nerve terminals, and also found in other tissue, including heart and skeletal muscles. α-syn does not have a stable 3D structure, enabling it to adopt different structure depending on the lipids and proteins that it is bound to. The N-terminus of α-syn allows the protein to bind and interact with phospholipid membranes in the cells. The central part of the protein can undergo a conformational change to β-sheet structure, forming oligomers, fibrils, and large aggregates, like β-amyloid. The two other synuclein isoforms, β-syn and γ-syn, inhibit the aggregation of α-syn.
α-synuclein functions as a chaperone in the formation of SNARE complexes, and is thus involved in vesicle trafficking. Monomeric α-syn blocks reversibly the voltage-dependent anion channel of the mitochondrial outer membrane at nanomolar concentrations. α-syn can also travel through the channel and inhibit the complex I activity of mitochondrial respiratory chain.
α-synucleinopathies are neurological disorders, where α-syn fibrils are accumulated intracellularly. The intracellular inclusions, called Lewy bodies, in Parkinson's disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA) are mainly composed of fibrillar α-syn aggregates. α-synucleinopathies include also multiple system atrophy and progressive supranuclear palsy. Lewy bodies may also contain tau protein in separate filaments. In PD and DLB the α-syn inclusions are mainly located in the neurons; in MSA the inclusions occur in oligodendroglial cells (Bauckneht et al., 2017).
Search for an optimal PET radiopharmaceutical for α-syn is ongoing (Kikuchi et al., 2010; Vernon et al., 2010; Eberling et al., 2013; Levigoureux et al., 2014; Zhang et al., 2014; Shah et al., 2014), but facing many challenges. The amount of amyloid-β can be much higher than the amount of α-syn; optimal radiopharmaceutical should bind very specifically to α-syn, and show little or no specificity towards amyloid-β and tau protein. Since most of the α-syn is located intracellularly, the radiopharmaceutical must be able to pass the blood-brain barrier and neuron cell membranes.
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Updated at: 2017-12-13
Created at: 2015-08-23
Written by: Vesa Oikonen