Abstract
Methamphetamine (METH), a highly addictive psychostimulant, is the second most widely used illicit drug. METH produces damage dopamine neurons and apoptosis via multiple inter-regulating mechanisms, including dopamine overload, hyperthermia, oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, protein degradation system dysfunction, and neuroinflammation. Increasing evidence suggests that chronic METH abuse is associated with neurodegenerative changes in the human brain and an increased risk of Parkinson’s disease (PD). METH use and PD may share some common steps in causing neurotoxicity. Accumulation of α-synuclein, a presynaptic protein, is the pathological hallmark of PD. Intriguingly, α-synuclein upregulation and aggregation are also found in dopaminergic neurons in the substantia nigra in chronic METH users. This suggests α-synuclein may play a role in METH-induced neurotoxicity. The mechanism of α-synuclein cytotoxicity in PD has attracted considerable attention; however, how α-synuclein affects METH-induced neurotoxicity has not been reviewed. In this review, we summarize the relationship between METH use and PD, interdependent mechanisms that are involved in METH-induced neurotoxicity and the significance of α-synuclein upregulation in response to METH use. The identification of α-synuclein overexpression and aggregation as a contributor to METH-induced neurotoxicity may provide a novel therapeutic target for the treatment of the deleterious effect of this drug and drug addiction.
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Abbreviations
- METH:
-
Methamphetamine
- PD:
-
Parkinson’s disease
- ATS:
-
Amphetamine-type stimulants
- DAT:
-
Dopamine transporter
- DA:
-
Dopamine
- VTA:
-
Ventral tegmental area
- TH:
-
Tyrosine hydroxylase
- VMAT2:
-
Vesicular monoamine transporter 2
- ER:
-
Endoplasmic reticulum
- UPS:
-
Ubiquitin–proteasome system
- DAQ:
-
DA-quinone
- ROS:
-
Reactive oxygen species
- NO:
-
Nitrogen monoxide
- PKCδ:
-
Protein kinase C-delta
- NAC:
-
Non-Aβ component
- JNK:
-
C-Jun N-terminal kinase
- NOS:
-
Nitric oxide synthase
- UCH-L1:
-
Ubiquitin carboxy-terminal hydrolase L1
- DDAH1:
-
Dimethylarginine dimethylaminohydrolase 1
- ADMA:
-
Asymmetric demethylated l-arginine
- SUMO-1:
-
Small ubiquitin modifier 1
- MeCP2:
-
Methyl-CpG binding protein 2
- DNMT1:
-
DNA methyltransferase 1
- SNP:
-
Single nucleotide polymorphisms
- DOPAC:
-
3,4-Dihydroxyphenylacetic acid
- HVA:
-
Homovanillic acid
- PDI:
-
Protein disulfide isomerase
- C/EBPβ:
-
CCAAT-enhancer binding protein β
- Trib3:
-
Tribbles pseudokinase 3
- CMA:
-
Chaperone-mediated autophagy
- Hsc70:
-
Heat shock cognate protein 70 kDa
- LAMP-2a:
-
Lysosome-associated membrane protein type 2a
- RNS:
-
Reactive nitrogen species
- AADC:
-
Aromatic amino acid decarboxylase
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This work was supported by National Nature Science Foundation (81771436), Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500), Shanghai Municipal Science, and Technology Major Project (2018SHZDZX05), Shanghai Clinical Research Center for Mental Health (19MC1911100), Shanghai Shenkang Hospital Development Center (SHDC2020CR3045B), Shanghai Intelligent Engineering Technology Research Center for Addiction and rehabilitation (19DZ2255200).
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Wu, M., Su, H. & Zhao, M. The Role of α-Synuclein in Methamphetamine-Induced Neurotoxicity. Neurotox Res 39, 1007–1021 (2021). https://doi.org/10.1007/s12640-021-00332-2
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DOI: https://doi.org/10.1007/s12640-021-00332-2