Complex network-driven view of genomic mechanisms underlying Parkinson's disease: analyses in dorsal motor vagal nucleus, locus coeruleus, and substantia nigra.

Beatriz Raposo Corradini,Edilaine Tampellini,Carlos Alberto Moreira-Filho,Lea Tenenholz Grinberg,José Marcelo Farfel,Priscila Iamashita

doi:10.1155/2014/543673

Abstract

Parkinson's disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient's group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide [1]
Network connectivity k for nondirected networks was calculated by k = 2L/N, where L stands for the number of edges and N for the number of nodes [24]. k values were 6.5 for vagal nucleus (VA)-CT
These analyses identified the highly connected hubs and hub modules that possibly play relevant roles in the brain aging and/or PD progression

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide [1]. Α-Synuclein is the most abundant protein found in Lewy bodies and usually aggregates in fibrillar structures [4]. The disease displays a caudal-rostral progression, starting in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the limbic structures and up to the neocortex [3, 5, 6]. This progression pathway is the basis of the widely accepted Braak staging model of PD [3, 5, 6]. Recent studies have shown that misfolded α-synuclein can be transferred between neurons in a prion-like manner and following the caudo-rostral progression pathway of Braak model [for revisions see [4, 7, 8]]

Methods

Results

Conclusion