What's the role of alpha-Synuclein?
α-Synuclein is a protein that is abundant in neurons and localized in vicinity to presynaptic terminals. Presynaptic terminals of nerves release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function. However, α-synucleins are prone to aggregate and can cause synaptic dysfunction1Vargas, K. J. et al. J. Neurosci. 34, 9364-9376 (2014). The accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases, such as Parkinson's disease or dementia with Lewy bodies2Galvin J. E. et al. Proc. Natl. Acad. Sci. U S A. 96, 13450-13455 (1999).
The Structure of alpha-Synuclein ensures its function
α-Synuclein is a small protein (140 amino acid
residues) encoded by the SNCA
(Synuclein Alpha) gene, expressed predominantly in brain. SNCA
is considered as the major causative gene involved in the early onset of familial Parkinson's disease3Bonini N. M. & Giasson B. I. Cell 123, 359-361 (2005). The α-synuclein protein (scheme 1) is composed of three distinct regions: (1) the N-terminal repeat region (residues 1-60), containing apolipoprotein lipid-binding motifs, which are predicted to form amphipathic helices conferring the propensity to form α-helical structures on membrane binding, (2) a central hydrophobic region (61-95), so-called NAC (non-Amyloid β component), which confers the β-sheet potential involved in protein aggregation, and (3) a carboxyl terminus that is highly negatively charged, and is prone to be unstructured.
Scheme 1 - structure of alpha-synuclein protein
Five point of mutations in SNCA
have been reported so far, responsible for autosomal dominant Parkinson's disease, A30P, E46K, H50Q, G51D and A53T localized to the amphipathic region of the protein. There is evidence that shows that the region from 32 to 58 of N-terminal lipid binding alpha helix domain of SNCA
is the most critical region. It is important not only from the evolutionary perspective but also for the stability and the proper conformation of the protein as well as crucial for the disease pathogenesis, harboring critical interaction sites4Siddiqui I. J. et al. Sci. Rep. 6, 24475 (2016).
Alpha-Synuclein acts through different pathways
α-Synuclein is involved in different pathways such as synaptic vesicle trafficking, and interacts with both proteins and lipid membranes to exert its function. In particular, at the synaptic level, α-synuclein behaves as a hub within protein interaction networks coordinating synaptic activity. α-Synuclein interacts with synaptic vesicle-associated proteins and tunes the release of neurotransmitters, in particular dopamine, by modulating the enzymes that are responsible of its synthesis (tyrosine hydroxylase), vesicular storage (vesicular monoamine transporter 2) and reuptake (dopamine transporter), respectively. In addition, α-synuclein can regulate synaptic vesicle transport by interacting with cytoskeletal components such as actin5Longhena F. et al. Int. J. Mol. Sci. 20, 141 (2019).
alpha-Synuclein plays a major role in Parkinson's disease
α-Synuclein represents the principal constituent of the main neuropathological characteristic of Parkinson's disease, the Lewy bodies. The Lewy bodies are cytoplasmic inclusions composed mainly of amyloid fibrils of α-synuclein. As a matter of fact, α-synuclein aggregates and forms insoluble fibrils in the dopaminergic neurons6Spillantini M. G. et al. Nature 388, 839-840 (1997). The NAC domain represents the critical determinant of the fibrillation process of the protein. It contains a 12-residue-long sequence (71-82) that seems to play a crucial role in the α-synuclein aggregation process7Martial B. et al. J. Phys. Chem. B 124, 3469-3481 (2020). Furthermore, the NAC region of the protein could even promote the in vivo formation of β-amyloid, which is the main component of the amyloid plaques found in the brains of people with Alzheimer's disease8Ueda K. et al. Proc. Natl. Acad. Sci. 90, 11282-11286 (1993).
alpha-Synuclein aggregation and misfolding cause detoration of neurons
The NAC peptide of α-synuclein self-aggregates via a nucleation-dependent kinetic mechanism9Han H. et al. Chem. Biol. 2, 163-169 (1995)and the aggregates possess a distinct fibrillar morphology (picture 1)10Iwai A. et al. Biochemistry 34, 10139-10145 (1995). Thus, α-synuclein shifts from its natively unfolded conformation to toxic oligomeric and fibrillary forms. However, the aggregation mechanism of α-synuclein is uncertain. The precursor of this aggregation and, ultimately, Lewy bodies formation can be caused by an intermediate structure of α-synuclein, rich in the β-sheet motif11Kim H. Y. et al. ChemBioChem 8, 1671-1674 (2007). In addition to the genetic mutations described previously, the ability of α-synuclein to change conformations can be affected by environmental stimuli such as reactive oxygen species, pH alterations or interacting proteins. These factors can lead to the formation of different toxic α-synuclein species such as oligomers or fibrils. By using advanced microscopy tools and correlation studies, researchers have been able to elucidate the inner structure of α-synuclein fibrils and the process of Lewy body formation. They observed that these fibrils adopt a Greek-key-β-sheet topology. This motif consists of four adjacent antiparallel β-sheet strands and their linking loops. It was named after a pattern common to Greek ornamental artwork. The Greek-key motif is the innermost core of α-synuclein central amino acids (71-82) composition12Tuttle M. et al. Nat. Struct. Mol. Biol. 23, 409-415 (2016).
Picture 1 - Solid state NMR determination of alpha-synuclein fibril structure
α-Synuclein misfolding and fibrillation cause progressive deterioration of neurons via disruption of the autophagy-lysosome system, mitochondrial dysfunction, endoplasmic reticulum stress, or dysregulation of calcium homeostasis13Michel P. P. et al. Neuron 90, 675-691 (2016). Furthermore, evidences suggest that α-synuclein can undergo a toxic conformational change and spread from cell to cell to seed and initiate the formation of aggregates in the newly 'contaminated' neurons14Tyson T. et al. J. Neurochem. 139, 275-289 (2016).
Towards a new understanding of Parkinson's disease?
It is generally accepted that Parkinson's disease results from a complex combination of genetic and environmental factors. Yet their respective influence on the disease initiation could likely vary from one individual to another. Thus, despites the convergence of the dopamine neurons degeneration in Parkinson's disease, it is conceivable that the number and respective importance of the death pathways may vary from one patient to another. Consequently, therapeutic strategies for preventing or slowing disease progression might be more efficient, if personalized to each case. With our strong expertise and leading position as peptides manufacturer, we offer a large selection of peptides, amino acid derivatives, and biochemicals. Our innovative peptides portfolio includes a variety of sequence modifications, and salt forms, as well as established bioactive peptides used in different applications such as Parkinson's disease and multiple sclerosis research.
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