Abstract
The principal causative pathology of Parkinson disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum in the brain. The information regarding the expression of neuropeptides in parkinsonism is very limited. Here we have elucidated striatal neuropeptide mechanisms in experimental parkinsonism using the unilateral 6-hydroxydopamine model to degenerate dopamine neurons. A thoroughly controlled sample preparation technique together with a peptidomics approach and targeted neuropeptide sequence collections enabled sensitive detection, identification, and relative quantitation of a great number of endogenous neuropeptides. Previously not recognized alterations in neuropeptide levels were identified in the unilateral lesioned mice with or without subchronic 3,4-dihydroxy-L-phenylalanine administration, the conventional treatment of Parkinson disease. Several of these peptides originated from the same precursor such as secretogranin-1, somatostatin, prodynorphin, and cholecystokinin. Disease-related biotransformation of precursors into individual peptides was observed in the experimental model of Parkinson disease. Several previously unreported potentially biologically active peptides were also identified from the striatal samples. This study provides further evidence that neuropeptides take part in mediating the central nervous system failure associated with Parkinson disease.
Highlights
The principal causative pathology of Parkinson disease is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum in the brain
Our results showed that a number of identified striatal peptides from different precursors, such as secretogranins, somatostatin, PPE-B, and cholecystokinin (CCK), were significantly altered in unilaterally 6-OHDA-lesioned mice with and without subchronic L-DOPA administration
The coupling of nano-LC to MS enabled detection and characterization of hundreds of endogenous peptide species simultaneously, and about 70 striatal neuropeptides were unambiguously identified and relatively quantified. Both known and previously unreported peptides derived from precursors such as secretogranin-1, somatostatin, PPE-B, and CCK were found to be differentially expressed
Summary
To compare all different treatment effects the data were analyzed using an ANOVA model with the four treatment groups as fixed factors and the samples and blocks as random factors (ANOVA2). Pairwise t testing between (SAL-LESION) and (SAL-INTACT), and between (LDOPA-LESION) and (LDOPA-INTACT), and t testing between (LDOPA-LESION) and (SAL-LESION) were performed on peptides significant in the ANOVAs. The reference samples were included for estimation of block effects. Tandem mass spectra were assigned sequences by searching them against three targeted sequence collections: SwePep precursors (123 protein entries), SwePep peptides (245 peptide entries), and SwePep prediction (3,413,034 peptide entries) as described previously [31] using X!Tandem (Version 2006.9.15.4) [32, 33]. If the falsepositive rate is over 1% the threshold suggested by the search engine needs to be adjusted for that sequence collection
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