Article

Pathways to neurodegeneration: Mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders

Department of Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, IN, USA
American Journal of Neurodegenerative Diseases 10/2013; 2(3):145-175.
Source: PubMed

ABSTRACT

The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.

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    • "Sporadic Alzheimer's disease (AD) represents the most prevalent form of dementia in the elderly, with several hypotheses being proposed to explain its etiopathogenesis. These hypotheses have focused either on the role of amyloid β, hyperphosphorylated and truncated tau protein, neuroinflammation, altered insulin signalization, impaired blood-brain barrier permeability, or other related factors and mechanisms[1,2]. However, despite such enormous scientific effort, the primary factors responsible for the development of AD still remain only vaguely defined. "
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    ABSTRACT: Brain norepinephrine (NE) plays an important role in the modulation of stress response and neuroinflammation. Recent studies indicate that in Alzheimer’s disease (AD), the tau neuropathology begins in the locus coeruleus (LC) which is the main source of brain NE. Therefore, we investigated the changes in brain NE system and also the immune status under basal and stress conditions in transgenic rats over-expressing the human truncated tau protein. Brainstem catecholaminergic cell groups (LC, A1, and A2) and forebrain subcortical (nucleus basalis of Meynert), hippocampal (cornu ammonis, dentate gyrus), and neocortical areas (frontal and temporal association cortices) were analyzed for NE and interleukin 6 (IL-6) mRNA levels in unstressed rats and also in rats exposed to single or repeated immobilization. Moreover, gene expression of NE-biosynthetic enzyme, tyrosine hydroxylase (TH), and several pro- and anti-inflammatory mediators were determined in the LC. It was found that tauopathy reduced basal NE levels in forebrain areas, while the gene expression of IL-6 was increased in all selected areas at the same time. The differences between wild-type and transgenic rats in brain NE and IL-6 mRNA levels were observed in stressed animals as well. Tauopathy increased also the gene expression of TH in the LC. In addition, the LC exhibited exaggerated expression of pro- and anti-inflammatory mediators (IL-6, TNFα, inducible nitric oxide synthases 2 (iNOS2), and interleukin 10 (IL-10)) in transgenic rats suggesting that tauopathy affects also the immune background in LC. Positive correlation between NE and IL-6 mRNA levels in cornu ammonis in stressed transgenic animals indicated the reduction of anti-inflammatory effect of NE. Our data thus showed that tauopathy alters the functions of LC further leading to the reduction of NE levels and exaggeration of neuroinflammation in forebrain. These findings support the assumption that tau-related dysfunction of LC activates the vicious circle perpetuating neurodegeneration leading to the development of AD.
    Preview · Article · Dec 2016 · Journal of Neuroinflammation
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    • "mitochondrial toxins such as rotenone, which is still widely used in bulk amounts for river treatment to fight fish parasites (Finlayson et al., 2014)) as well as genetic factors (e.g. PARK-genes), as summarized in detail in excellent reviews (Hirsch and Hunot, 2009; Hardy, 2010; Alves da Costa and Checler, 2011; Collier et al., 2011; Gasser et al., 2011; Surmeier et al., 2012; Moskvina et al., 2013; Ramanan and Saykin, 2013; Singleton et al., 2013; Sulzer and Surmeier, 2013). In essence, activity-related cellular Ca 2+ load, mitochondrial DNA deletions and mitochondrial dysfunction, as well as oxidative and metabolic stress are particularly important trigger factors for PD (Bender et al., 2006; Guzman et al., 2010; Alves da Costa and Checler, 2011; Collier et al., 2011; Shulman et al., 2011; Watfa et al., 2011; Coskun et al., 2012; Surmeier and Schumacker, 2013; Checler and Alves da Costa, 2014; Parlato and Liss, 2014; Phillipson, 2014). "
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    • "In addition, guanine (CAG) n expansions in the ATXN2 gene and hexanucleotide repeat expansions in the C9ORF72 gene are involved in both ALS and PD (Furtado et al., 2004; O'Dowd et al., 2012; Ross et al., 2011). Single-nucleotide polymorphisms (SNPs) have an important function in the development of neurodegenerative disorders (Ramanan and Saykin, 2013). For example, polymorphisms in the promoter Rep1 of alpha-synuclein (SNCA), polyglutamine repeats in ATXN2, and Val343Ala in coenzyme Q2 4-hydroxybenzoate polyprenyltransferase increase the risk for PD (Mata et al., 2010), ALS (Daoud et al., 2011), and MSA (Collaboration, 2013), respectively. "
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    Full-text · Article · Jul 2014 · Neurobiology of Aging
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