title: Copy number variability in Parkinson's disease: assembling the puzzle through a systems biology approach.
abstract: Parkinson's disease (PD), the second most common progressive neurodegenerative disorder of aging, was long believed to be a non-genetic sporadic origin syndrome. The proof that several genetic loci are responsible for rare Mendelian forms has represented a revolutionary breakthrough, enabling to reveal molecular mechanisms underlying this debilitating still incurable condition. While single nucleotide polymorphisms (SNPs) and small indels constitute the most commonly investigated DNA variations accounting for only a limited number of PD cases, larger genomic molecular rearrangements have emerged as significant PD-causing mutations, including submicroscopic Copy Number Variations (CNVs). CNVs constitute a prevalent source of genomic variations and substantially participate in each individual's genomic makeup and phenotypic outcome. However, the majority of genetic studies have focused their attention on single candidate-gene mutations or on common variants reaching a significant statistical level of acceptance. This gene-centric approach is insufficient to uncover the genetic background of polygenic multifactorial disorders like PD, and potentially masks rare individual CNVs that all together might contribute to disease development or progression. In this review, we will discuss literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will analyze the most frequent copy number changes in familiar PD genes and provide a "systems biology" overview of rare individual rearrangements that could functionally act on commonly deregulated molecular pathways. Assessing the global genome-wide burden of CNVs in PD patients may reveal new disease-related molecular mechanisms, and open the window to a new possible genetic scenario in the unsolved PD puzzle.
authors.affiliation: Institute of Neurological Sciences, National Research Council, Catania, Italy.|Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: La Cognata
authors.affiliation: Institute of Neurological Sciences, National Research Council, Catania, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Morello
authors.affiliation: Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Velia
authors.initials: V
authors.lastname: D'Agata
authors.affiliation: Institute of Neurological Sciences, National Research Council, Catania, Italy. sebastiano.cavallaro@cnr.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cavallaro
mesh_terms: D002872:Chromosome Deletion; D056915:DNA Copy Number Variations; D056426:Genetic Loci; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000071617:Protein Deglycase DJ-1 / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics; D049490:Systems Biology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: C514983:ATP13A2 protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D006180:Proton-Translocating ATPases