Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

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.

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy

“…Generation of free nitric oxide can perpetuate posttranslational modifications of aggregation-prone proteins such as tau (Reynolds et al, 2006;Reyes et al, 2008;Reyes et al, 2011;Reyes et al, 2012), amyloid ␤ (Kummer et al, 2011), and ␣-synuclein (Kotzbauer et al, 2004Yu et al, 2010;Liu et al, 2011).…”

“…Conversely, in A␤-depositing transgenic mice devoid of iNOS, exaggerated AD-like pathology suggests that a critical balance between Arg1 and NOS determines the acceleration vs mitigation of amyloid deposition (Colton et al, 2006). Nitration of tau has also been observed during tauopathies and other aggregation-prone proteins such as ␣-synuclein are also nitrated (Reynolds et al, 2006;Reyes et al, 2008;Yu et al, 2010;Reyes et al, 2011;Reyes et al, 2012).…”

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

“…Interestingly, tyrosine nitration of α-synuclein is a common modification found among different synucleinopathies such as PD, multiple system atrophy and dementia with Lewy bodies (Giasson et al 2000). Nitrated α-synuclein accumulates within the brain parenchyma of PD patients and animal models (Giasson et al 2000;Benner et al 2008;Yu et al 2010). Moreover, a robust antigen-specific immune response against nitrated forms of α-synuclein has been observed in mice intoxicated with MPTP (Benner et al 2008).…”

Vaccination strategies for Parkinson disease

“…171 They further showed in the MPTP model that N-4YSyn immunization induced a Th17 cell response and resulted in Treg dysfunction, but adoptive transfer of Treg from VIP immunized animals attenuated Nα-syn induced microglial inflammatory responses and led to nigrostratial protection in the same model. 101 Nα-syn is known to induce cell death in SH-SY5Y cells 172,173 and to have a pathological effect on α-syn influencing its aggregation, [174][175][176] but it is also accumulated in DAergic neurons of the SN of monkeys as a normal result of aging. 177 Thus Nα-syn could help break immune tolerance as it accumulates with age and ultimately induce neurodegeneration.…”