Defects in the striatal neuropeptide Y system in X-linked dystonia-parkinsonism

Abstract

Neuropeptide Y is a novel bioactive substance that plays a role in the modulation of neurogenesis and neurotransmitter release, and thereby exerts a protective influence against neurodegeneration. Using a sensitive immunohistochemical method with a tyramide signal amplification protocol, we performed a post-mortem analysis to determine the striatal localization profile of neuropeptide Y in neurologically normal individuals and in patients with X-linked dystonia-parkinsonism, a major representative of the neurodegenerative diseases that primarily involve the striatum. All of the patients examined were genetically verified as having X-linked dystonia-parkinsonism. In normal individuals, we found a scattered distribution of neuropeptide Y-positive neurons and numerous nerve fibres labelled for neuropeptide Y in the striatum. Of particular interest was a differential localization of neuropeptide Y immunoreactivity in the striatal compartments, with a heightened density of neuropeptide Y labelling in the matrix compartment relative to the striosomes. In patients with X-linked dystonia-parkinsonism, we found a significant decrease in the number of neuropeptide Y-positive cells accompanied by a marked loss of their nerve fibres in the caudate nucleus and putamen. The patients with X-linked dystonia-parkinsonism also showed a lack of neuropeptide Y labelling in the subventricular zone, where a marked loss of progenitor cells that express proliferating cell nuclear antigen was found. Our results indicate a neostriatal defect of the neuropeptide Y system in patients with X-linked dystonia-parkinsonism, suggesting its possible implication in the mechanism by which a progressive loss of striatal neurons occurs in X-linked dystonia-parkinsonism.

Spinal Central Effects of Peripherally Applied Botulinum Neurotoxin A in Comparison between Its Subtypes A1 and A2

“…The primary antibodies used were mouse mAb against BoNT/A-cleaved SNAP-25 (1:5,000; GENTAUR Molecular) or rabbit polyclonal antibody against SNAP-25 (1:20,000; GeneTex). Bound antibodies were visualized with the Histofine Simple Stain Kit (Nichirei, Tokyo, Japan) and the tyramide signal amplification (TSA) system with Cyanine 3 or Fluorescein (Perkin Elmer LAS), according to the methods reported previously (20, 21). For dual antigen detection, the sections stained for BoNT/A-cleaved-SNAP-25 were incubated in 0.1 M glycine–HCl (pH 2.2) at room temperature for 30 min.…”

X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B

“…There have been limited analyses of post-mortem brain tissue which have described XDP-related neuropathology (Goto et al, 2013; Goto et al, 2005; Waters et al, 1993) and expression of certain transcripts within the striatum (Makino et al, 2007), but to date there has been little information about specific cellular defects which might contribute to disease pathogenesis. This gap in knowledge has no doubt been exacerbated by the challenges in understanding the genetics of XDP.…”

“…The disease has been associated with the loss of medium spiny neurons within the striatum (Goto et al, 2013; Goto et al, 2005), although the involvement of other brain regions has not been definitively excluded, and the mechanisms underlying XDP neuropathology are not known. XDP primarily affects men from the island of Panay, Philippines, where the reported disease prevalence is approximately 5.74 cases per 100,000 individuals (Lee et al, 2011).…”

Non-motor symptoms in genetically defined dystonia: Homogenous groups require systematic assessment

“…Monoamine involvement has also been implicated in DYT12 cohorts with altered levels detected in CSF studies and immunostaining localizing the NA/K-ATPase to the basal ganglia of mouse models [38,45]. Neuropathological studies of DYT3 cases demonstrated neuronal loss and astrocytosis in caudate and putaminal regions, with corresponding reduced neuropeptide Y labelling [46].…”