Abstract
BackgroundThe pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated α-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of α-synuclein is relevant to the pathogenesis of PD is unknown.Methodology/Principal FindingsIn this study, effect of nitrated α-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-α-synuclein intracellular. We provide evidence to show that the nitrated α-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated α-synuclein. Moreover, we show that administration of nitrated α-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D2R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated α-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified α-synuclein had significantly less severe behavioral effects.Conclusions/SignificanceOur results provide evidence that α-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.
Highlights
Parkinson’s disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of neuronal inclusions known as Lewy bodies and Lewy neurites within DA neurons of the substantia nigra [1]
Missense mutations in asynuclein and duplications or triplications of the locus cause PD [2,3,4,5,6,7]. a-Synuclein is involved in dopamine neurotransmission, including release and reuptake [8,9], and affects enzymes involved in chromatin remodeling [10]. a-Synuclein comprises a major component of Lewy bodies and Lewy neurites in DA neurons in the substantia nigra of patients with PD, and is a major constituent of other types of inclusions found in a group of diseases, collectively known as ‘synucleinopathies’ [11]
Anti-HA Western blotting further confirmed that treating SYN with SIN-1 did not change the electrophoretic properties of SYN, and showed that the N-SYN product is slightly larger than SYN (Figure 1A, middle)
Summary
Parkinson’s disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of neuronal inclusions known as Lewy bodies and Lewy neurites within DA neurons of the substantia nigra [1]. A-Synuclein comprises a major component of Lewy bodies and Lewy neurites in DA neurons in the substantia nigra of patients with PD, and is a major constituent of other types of inclusions found in a group of diseases, collectively known as ‘synucleinopathies’ [11]. The pathology of Parkinson’s disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated a-synuclein are demonstrated in the signature inclusions of Parkinson’s disease. Whether the nitration of a-synuclein is relevant to the pathogenesis of PD is unknown
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