Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

Abstract

Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons.

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson’s Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment

“…MPTP in the brain is converted to toxic metabolite MPP+ by selectively inhibiting complex I of the mitochondrial electron transport chain. Mitochondrial dysfunction results in ATP disturbance, abnormal lipid and amino acid metabolism [ 10 ]. Anticholinergic drugs and other medications are used to treat PD.…”

Editorial of the Special Issue: Recent Advances in Understanding of the Role of Synuclein Family Members in Health and Disease

“…The latest research revealed and delineated their role in the optimisation of dopamine uptake through synaptic vesicles and suggested that β-synuclein, rather than α-synuclein, potentiates this uptake [ 1 , 11 ]. These were discussed in connection with the different sensitivity of various synuclein deficient mouse models to MPTP toxicity [ 12 ]. In this review, the authors analysed available published data on how single, double, and triple knockouts of synuclein family members affect animal sensitivity to MPTP toxicity and attempted to explain the impact of α-, β-, and γ-synuclein on the mechanisms of MPTP and its active derivate, MPP+, toxicity on dopaminergic neurones.…”