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.
Keywords: Dopamine; Methamphetamine; Neurotoxicity; Parkinson’s disease; α-synuclein.