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

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA
American Journal of Neurodegenerative Diseases 10/2013; 2(3):145-175.
Source: PubMed


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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    • "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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    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.037 · 3.36 Impact Factor
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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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    ABSTRACT: Previous studies found that polymorphisms rs2736990 and rs356220 in the alpha-synuclein (SNCA) gene increase the risk for Parkinson's disease (PD) in a Caucasian population. In consideration of the overlapping of clinical manifestations and pathologic characteristics among PD, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA), the possible associations of these 2 polymorphisms and 3 neurodegenerative diseases were studied in the Chinese population. A total of 1011 PD, 778 sporadic ALS (SALS), 264 MSA patients, and 721 healthy controls (HCs) were studied. All subjects were genotyped for the 2 polymorphisms using polymerase chain reaction and direct sequencing. Significant differences in the genotype frequencies (p = 0.0188 and 0.0064, respectively) and minor allele frequencies (MAFs) (p = 0.0065 and 0.0095, respectively) of rs2736990 and rs356220 were observed between the PD patients and HCs. Moreover, significant differences were found between the early-onset PD patients (<50 years) and matched controls but not in the late-onset PD patients (≥50 years). However, no differences were observed between subgroups with regard to clinical features, such as sex, onset symptoms (tremor or rigidity), cognition (normal or abnormal), and anxiety and depression (presence or absence). No significant differences were found in the genotype frequencies and MAFs of these 2 single-nucleotide polymorphisms between SALS patients and HCs and between MSA patients and HCs. No significant differences were found between subgroups with regard to the clinical presentation of SALS and MSA. Our results show that rs2736990 and rs356220 in SNCA decreased the risk for PD in a Chinese population. These candidate polymorphisms were unlikely to be the causes of SALS and MSA in this population.
    Neurobiology of Aging 07/2014; 35(12). DOI:10.1016/j.neurobiolaging.2014.07.014 · 5.01 Impact Factor
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    • "In this review, the major neuropsychiatric and behavioral symptoms of AD are reviewed with emphasis on how these symptoms may illuminate disease pathogenesis or provide prognostic information. Alzheimer's dementia is the end result of multiple pathogenic processes including aberrant amyloid processing [4] [5], changes in lipid metabolism due to apolipoprotein E (APOE) risk alleles [6] [7], tau hyperphosphorylation [8], protein misfolding and endoplasmic reticulum (ER) stress [9], vascular dysfunction [10], oxidative stress and mitochondrial dysfunction [11] [12], neurotrophic factor dysregulation [13], disrupted leptin signaling [14], fibrin clots [15], and processes mediated by a myriad of other AD-associated gene [16], and the pathogenic processes also occurred in major neuropsychiatric symptoms (Figure 1). It is likely that these processes target nonoverlapping neural networks, accounting for difference in disease progression and the variability in neuropsychiatric symptoms. "
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    ABSTRACT: Neuropsychiatric symptoms (NPS) such as depression, apathy, aggression, and psychosis are now recognized as core features of Alzheimer's disease (AD), and there is a general consensus that greater symptom severity is predictive of faster cognitive decline, loss of independence, and even shorter survival. Whether these symptoms result from the same pathogenic processes responsible for cognitive decline or have unique etiologies independent of AD-associated neurodegeneration is unclear. Many structural and metabolic features of the AD brain are associated with individual neuropsychiatric symptoms or symptom clusters. In addition, many genes have been identified and confirmed that are associated with symptom risk in a few cases. However, there are no single genes strongly predictive of individual neuropsychiatric syndromes, while functional and structural brain changes unique to specific symptoms may reflect variability in progression of the same pathological processes. Unfortunately, treatment success for these psychiatric symptoms may be lower when comorbid with AD, underscoring the importance of future research on their pathobiology and treatment. This review summarizes some of the most salient aspects of NPS pathogenesis.
    BioMed Research International 07/2014; 2014(5):927804. DOI:10.1155/2014/927804 · 1.58 Impact Factor
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