112 7 Prospective
While the overexpression of NOS impairs autophagic flux, the inhibition of
NO production induces autophagy. The NOS inhibitor l-NMMA also induces
autophagy but is independent on mTORC1 activity or Bcl-2 phosphorylation.
Interestingly, deprival of NO by l-NMMA or the endogenous dominant-negative
NOS regulator NOS 4 reduces mutant huntingtin aggregation and neurodegenera-
tion in the fruit fly Huntington disease model.
Accumulation of amyloid-β and tau is an invariant feature of Huntington dis-
ease, but RAP-induced autophagy allows a significant reduction in amyloid-β
levels (Caccamo et al. 2010 ). Although S-nitrosylation is able to interpret the
NO-enhanced autophagy and alleviated neurodegeneration, it has not determined
whether S-nitrosylation is a general mechanism of NO-impaired autophagy or
only represents a randomized event. Cho et al. ( 2009 ) have demonstrated that
the S-nitrosylation of dynamin-related protein 1 (DRP1) rich in the brains of
Alzheimer’s disease patients increases GTPase activity and mediates β-amyloid-
related mitochondrial fission and neuronal injury. However, Bossy et al. ( 2010 )
have refuted that the S-nitrosylation of DRP1 does not affect GTPase activity and
is not specific to Alzheimer’s disease. This discrepancy may be attributed to the
reversible feature of S-nitrosylation, but another possibility is the alternative modi-
fications of DPR1 or downstream proteins by S-nitrosylation.
NO can also lead to the nitration of tyrosine and other amino acid residues
through modification by ONOO− except for the S-nitrosylation of cysteine.
Treatment of rats or mice by LPS in vivo or ONOO− in vitro significantly pro-
motes the formation of 3-nitrotyrosine in insulin receptor substrate 1 (IRS-1) and
reduces the insulin-dependent tyrosine phosphorylation, eventually leading to
the insulin resistance of skeletal muscles (Pilon et al. 2010 ). The enhanced 3NT
modification of mitochondrial proteins occurs with aging, in which the nitration
of F1-ATPase at tyrosine 269 leads to ADP binding to the enzyme’s active center,
and is associated with a moderate impairment of the mitochondrial function (Lam
et al. 2009 ). If the nitration of tyrosine occurs globally, it seems reasonable to
interpret the results of Sarkar et al. ( 2011 ) by the nitrosative inactivation of sepa-
rated signaling proteins of the autophagy machinery. Besides, l-NMMA abrogates
neurodegeneration perhaps through directly blocking the misfolding and aggrega-
tion of proteins such as Huntingtin due to S-nitrosylation or 3-nitration.
Indeed, S-nitrosylation of protein-disulfide isomerase or the E3 ubiquitin ligase
parkin is found to initiate protein misfolding and aggregation in Parkinson’s dis-
ease (Gu et al. 2010 ). Previously, overexpression of nNOS was detected in the
brains of Parkinson’s disease patients (Eve et al. 1998 ). The existence of 3NT
was found in the core of Lewy bodies, the pathological hallmark of Parkinson’s
disease progression (Good et al. 1998 ). The observation of nNOS was correlated
with the presence of 3NT in circulating neutrophils from Parkinson’s disease
patients (Gatto et al. 2000 ). Recent studies have shown that α-synuclein is one of
the major building blocks in Lewy bodies (Ischiropoulos 2009 ). It is apparent that
the majority of Lewy bodies and protein inclusions contain nitrated and oxidized
α-synuclein, indicating that oxidation is participated in the formation of these inclu-
sions. Additionally, nitration or nitrosylation of ubiquitin E3-ligases can result