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).

PET radiopharmaceuticals

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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References:

Eberling JL, Dave KD, Frasier MA. &alpha-synuclein imaging: a critical need for Parkinson's disease research. J Parkinson's Dis. 2013; 3: 565-567. doi: 10.3233/JPD-130247

Gallegos S, Pacheco C, Peters C, Opazo CM, Aguayo LG. Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease. Front Neurosci. 2015;9:59. doi: 10.3389/fnins.2015.00059.

Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE. α-synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2013; 73(2): 155-169. doi: 10.1002/ana.23746.

Mak E, Su L, Williams GB, O'Brien JT. Neuroimaging characteristics of dementia with Lewy bodies. Alzheimers Res Ther. 2014; 6(2): 18. doi: 10.1186/alzrt248.

Marques O, Outeiro TF. Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis. 2012; 3: e350. doi: 10.1038/cddis.2012.94.

Mullin S, Schapira A. α-synuclein and mitochondrial dysfunction in Parkinson's disease. Mol Neurobiol. 2013; 47: 587-597. doi: 10.1007/s12035-013-8394-x.

Rostovtseva TK, Gurnev PA, Protchenko O, Hoogerheide DP, Yap TL, Philpott CC, Lee JC, Bezrukov SM. α-synuclein shows high affinity interaction with voltage-dependent anion channel, suggesting mechanisms of mitochondrial regulation and toxicity in Parkinson disease. J Biol Chem. 2015; 290(30): 18467-18477. doi: 10.1074/jbc.M115.641746.

Shah M, Seibyl J, Cartier A, Bhatt R, Catafau AM. Molecular imaging insights into neurodegeneration: focus on α-synuclein radiotracers. J Nucl Med. 2014; 55(9): 1397-1400. doi: 10.2967/jnumed.113.136515.

Vernon AC, Ballard C, Modo M. Neuroimaging for Lewy body disease: Is the in vivo molecular imaging of α-synuclein neuropathology required and feasible? Brain Res Rev. 2010; 65: 28-55. doi: 10.1016/j.brainresrev.2010.05.006.



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Updated at: 2017-12-13
Created at: 2015-08-23
Written by: Vesa Oikonen