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Interaction between Neuromelanin and Alpha-Synuclein in Parkinson's Disease.

Xu S, Chan P - Biomolecules (2015)

Bottom Line: Recently, the role of NM in inducing α-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD.NM may be responsible for PD and age-associated increase and aggregation in α-syn.Here, we reviewed our previous study and other recent findings in the area of interaction between NM and α-syn.

View Article: PubMed Central - PubMed

Affiliation: Beijing Institute of Geriatrics, Xuanwu Hospital of Capital University of Medical Sciences, No.45 changchun St., Xicheng District, Beijing 100053, China. xushngli_xw@163.com.

ABSTRACT
Parkinson's disease (PD) is a very common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) into Lewy body (LB) inclusions and the loss of neuronmelanin (NM) containing dopamine (DA) neurons in the substantia nigra (SN). Pathological α-syn and NM are two prominent hallmarks in this selective and progressive neurodegenerative disease. Pathological α-syn can induce dopaminergic neuron death by various mechanisms, such as inducing oxidative stress and inhibiting protein degradation systems. Therefore, to explore the factors that trigger α-syn to convert from a non-toxic protein to toxic one is a pivotal question to clarify the mechanisms of PD pathogenesis. Many triggers for pathological α-syn aggregation have been identified, including missense mutations in the α-syn gene, higher concentration, and posttranslational modifications of α-Syn. Recently, the role of NM in inducing α-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD. NM may be responsible for PD and age-associated increase and aggregation in α-syn. Here, we reviewed our previous study and other recent findings in the area of interaction between NM and α-syn.

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Related in: MedlinePlus

Model of possible interactions between α-synuclein (α-syn) and neuromelanin (NM). (a) NM induces the expression and aggregation of α-syn; (b) dopamine (DA) is synthesized in the cytoplasm by the action of tyrosine hydroxylase (TH) and amino acid decarboxylase (AADC). α-Syn has been shown to regulate the activity of TH and AADC; (c) DA is reuptake via the dopamine transporter (DAT). Studies in cell culture systems have shown that α-syn is necessary for the trafficking of DAT to the cell surface. (d) Once synthesized, DA is immediately sequestered into vesicles by the vesicular monoamine transporter 2 (VMAT2). Several lines of evidence suggest that α-syn is involved in regulating storage, release and presynaptic vesicle cycling. (e) High levels of α-syn and cytosolic DA cause selective DA neuron death and eventually lead to PD.
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biomolecules-05-01122-f002: Model of possible interactions between α-synuclein (α-syn) and neuromelanin (NM). (a) NM induces the expression and aggregation of α-syn; (b) dopamine (DA) is synthesized in the cytoplasm by the action of tyrosine hydroxylase (TH) and amino acid decarboxylase (AADC). α-Syn has been shown to regulate the activity of TH and AADC; (c) DA is reuptake via the dopamine transporter (DAT). Studies in cell culture systems have shown that α-syn is necessary for the trafficking of DAT to the cell surface. (d) Once synthesized, DA is immediately sequestered into vesicles by the vesicular monoamine transporter 2 (VMAT2). Several lines of evidence suggest that α-syn is involved in regulating storage, release and presynaptic vesicle cycling. (e) High levels of α-syn and cytosolic DA cause selective DA neuron death and eventually lead to PD.

Mentions: In conclusion, no matter what is the trigger, NM and α-syn are likely to form a vicious cycle of mutual promotion, eventually the untoward cycle results in the death of DA neurons in PD (see Figure 2). In sporadic PD, age-related accumulation of NM induces α-syn expression and aggregation. On the other hand, accumulated α-syn may promote the biosynthesis of NM by increasing the levels of cytosolic DA. In familial PD, the mutants of α-syn also can trigger the accumulation of NM and start this vicious cycle.


Interaction between Neuromelanin and Alpha-Synuclein in Parkinson's Disease.

Xu S, Chan P - Biomolecules (2015)

Model of possible interactions between α-synuclein (α-syn) and neuromelanin (NM). (a) NM induces the expression and aggregation of α-syn; (b) dopamine (DA) is synthesized in the cytoplasm by the action of tyrosine hydroxylase (TH) and amino acid decarboxylase (AADC). α-Syn has been shown to regulate the activity of TH and AADC; (c) DA is reuptake via the dopamine transporter (DAT). Studies in cell culture systems have shown that α-syn is necessary for the trafficking of DAT to the cell surface. (d) Once synthesized, DA is immediately sequestered into vesicles by the vesicular monoamine transporter 2 (VMAT2). Several lines of evidence suggest that α-syn is involved in regulating storage, release and presynaptic vesicle cycling. (e) High levels of α-syn and cytosolic DA cause selective DA neuron death and eventually lead to PD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496713&req=5

biomolecules-05-01122-f002: Model of possible interactions between α-synuclein (α-syn) and neuromelanin (NM). (a) NM induces the expression and aggregation of α-syn; (b) dopamine (DA) is synthesized in the cytoplasm by the action of tyrosine hydroxylase (TH) and amino acid decarboxylase (AADC). α-Syn has been shown to regulate the activity of TH and AADC; (c) DA is reuptake via the dopamine transporter (DAT). Studies in cell culture systems have shown that α-syn is necessary for the trafficking of DAT to the cell surface. (d) Once synthesized, DA is immediately sequestered into vesicles by the vesicular monoamine transporter 2 (VMAT2). Several lines of evidence suggest that α-syn is involved in regulating storage, release and presynaptic vesicle cycling. (e) High levels of α-syn and cytosolic DA cause selective DA neuron death and eventually lead to PD.
Mentions: In conclusion, no matter what is the trigger, NM and α-syn are likely to form a vicious cycle of mutual promotion, eventually the untoward cycle results in the death of DA neurons in PD (see Figure 2). In sporadic PD, age-related accumulation of NM induces α-syn expression and aggregation. On the other hand, accumulated α-syn may promote the biosynthesis of NM by increasing the levels of cytosolic DA. In familial PD, the mutants of α-syn also can trigger the accumulation of NM and start this vicious cycle.

Bottom Line: Recently, the role of NM in inducing α-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD.NM may be responsible for PD and age-associated increase and aggregation in α-syn.Here, we reviewed our previous study and other recent findings in the area of interaction between NM and α-syn.

View Article: PubMed Central - PubMed

Affiliation: Beijing Institute of Geriatrics, Xuanwu Hospital of Capital University of Medical Sciences, No.45 changchun St., Xicheng District, Beijing 100053, China. xushngli_xw@163.com.

ABSTRACT
Parkinson's disease (PD) is a very common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) into Lewy body (LB) inclusions and the loss of neuronmelanin (NM) containing dopamine (DA) neurons in the substantia nigra (SN). Pathological α-syn and NM are two prominent hallmarks in this selective and progressive neurodegenerative disease. Pathological α-syn can induce dopaminergic neuron death by various mechanisms, such as inducing oxidative stress and inhibiting protein degradation systems. Therefore, to explore the factors that trigger α-syn to convert from a non-toxic protein to toxic one is a pivotal question to clarify the mechanisms of PD pathogenesis. Many triggers for pathological α-syn aggregation have been identified, including missense mutations in the α-syn gene, higher concentration, and posttranslational modifications of α-Syn. Recently, the role of NM in inducing α-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD. NM may be responsible for PD and age-associated increase and aggregation in α-syn. Here, we reviewed our previous study and other recent findings in the area of interaction between NM and α-syn.

Show MeSH
Related in: MedlinePlus