The definition of α-synuclein

α-synuclein is a soluble protein expressed in the pre-synaptic and perinuclear regions of the central nervous system. It is closely related to the pathogenesis and related dysfunction of Parkinson's disease. And α-synuclein is the main component of Louis's body.

The properties of α-synuclein

The structure of the α-synuclein is largely dependent on its intracellular environment and exhibits different structures such as monomers, oligomers, fibrils and fibers, and the synaptic nuclei Proteins are easily aggregated to form insoluble fibrin deposits, eventually leading to neuronal cell death. The study of human genetics has demonstrated the predominant pathogenicity of α-synuclein gene mutations in familial Parkinson's disease, and the aggregation of α-synuclein has a similar prion-like cell-to-cell transmission.

The discovery of α-synuclein

Synuclein was originally discovered in 1988 by Maroteaux et al. Using purified anticholinergic vesicle antibodies found in the sturgeon and identified as pre-synaptic terminals and nucleus, and the same synuclein is also (Aa61-65), which is named as non-beta-amyloid structure (NAC), is found in the senile plaques of the age group, but not with high levels of beta-amyloid. A total of three synaptic nucleoproteins have been identified as α, β, γ, respectively, in which only the α-synuclein contains the NAC domain and participates in the formation of Lewy bodies, gene mutations of α-synuclein and Amplification can cause familial Parkinson's disease. So far, five sites have been found to be A53T, A30P, E46K, G51D and H50Q.

The function of α-synuclein

Inhibition of phospholipase D2 activity: Jenco et al in vitro study found that bovine brain contains a thermal stability factor can inhibit the activity of phospholipase D2, and finally proved that the factor is mixed with α, β synuclein homologues; phospholipids Enzyme D2 can catalyze the hydrolysis of lecithin and show the regulation of cytoskeleton recombination and plasma membrane endocytosis, so α-synuclein can affect the structure and stability of cell membrane.

Inhibition of the release of dopaminergic neurotransmitters: Abeliovich et al. Demonstrated that the substantia nigra of mice induced by α-synuclein knockout increased the dopamine release under paired electrical stimulation, while the physiological activity of the mice was not affected and the brain Neuron structure remains intact, but alpha-synuclein may play a protective role under pathological conditions.

Binding to synphilin-1 protein: Engelender et al. Used yeast two-hybrid technique to find synphilin-1 protein as a regulatory molecule to anchor α-synuclein into the protein molecules involved in vesicular transport and cytoskeletal function; synphilin-1 protein Is a 90 kDa intracellular protein containing ANKYRIN-like repeat units, a helical domain and possibly ATP / GTP binding sites; Kawamata et al. Demonstrated the C-terminus of the alpha-synuclein with fluorescence resonance energy transfer (FRET) The C-terminus of synphilin-1 is tightly connected, and the N-terminal link between them is weak.

Regulation of synaptic membrane vesicle release: Murphy and other use of antisense oligodeoxynucleotides to interfere with in vitro cultured mouse hippocampal neurons α-synuclein gene expression, found that the end of the synaptic terminal release vesicles The decrease in number indicates that α-synuclein can affect the release of synaptic vesicles.

Fatty acid-linked protein-like effects: Sharon et al. Found that α-synuclein can transport free fatty acids between the aqueous and membrane phospholipid components of neurons, suggesting that the α-synuclein may be a member of the family of fatty acid connexins The

Chaperone protein-like effects: Kim et al. Found that α-synuclein exhibits a similar chaperone-like action to prevent glutathione S-transferase (GST) and aldolase from precipitating under heat conditions and also prevent di Thioureitol (DTT) induces the precipitation of alpha-lactalbumin and calf serum proteins, which may bind to the hydrophilic domain of the protein in the process of deposition and stabilize the structure of the alpha-synuclein, damage.

Anti-apoptotic effects: Alves da Costa et al. Found that wild-type alpha-synuclein can significantly attenuate three different apoptotic inducers of astaxanthin, similar to the simulated transfected TSM1 neurons The activation of paclitaxel and ceramide C2 on intracellular caspase activity may also be related to the chaperone-like protein effect of α-synuclein. Ostrerova et al. Also found that the structure of α-synuclein and Function similar to the 14-3-3 protein, with PKC, BAD, ErK and other proteins involved in apoptosis control: Chandra and other found to improve the expression of α-synuclein can reduce the CSPα-deficient mice nerve endings Burré et al. Also confirmed that α-synuclein was able to bind directly to the SNARE complex through vesicle-associated membrane protein 2 (VAMP2) and promote its polymerization.

Participate in learning and memory: Kokhan et al. Demonstrated that alpha-synuclein knockout mice had lower scores in active and passive avoidance trials and Morris water maze tests than in normal controls, given that alpha-synuclein Hippocampus back to the high expression, so α-synuclein may be through the regulation of synaptic plasticity affect the animal's learning and memory ability.

The summary of α-synuclein

Since 1997, α-synuclein has been found to be associated with familial Parkinson's disease (SCNA) mutations and the main components of Lewy bodies, it has become the focus in the molecular pathogenesis of Parkinson's disease. The structure, function and pathogenesis of α-synuclein are more and more comprehensive.

And the treatment of Parkinson's disease is rather limited, can only improve the symptoms and can not prevent the progression of the disease; in view of α-synuclein for the pathogenesis of Parkinson's disease, developed for the reduction of its synthesis, secretion, Increasing the treatment of pathogenic oligomers has become the most promising tool for conception of Parkinson's disease, such as the use of small interfering RNA (miRNA) to attenuate the expression of SNCA gene, inhibit the SNCA gene promoter, enhance the self- Body function, to promote α-synuclein and chaperone protein binding, reduce post-transcriptional modification, stable free state of α-synuclein and so on.

Of course, a more detailed understanding of the pathogenic mechanisms of alpha-synuclein will provide more treatment direction and prospects