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      DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

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          Abstract

          We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ +/− mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.

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          Gene regulation and DNA damage in the ageing human brain.

          Tao Lu, Ying Pan, Shyan-Yuan Kao … (2004)
          The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.
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            Alzheimer’s disease drug-development pipeline: few candidates, frequent failures

            Jeffrey L Cummings, Travis Morstorf, Kate Zhong (2014)
            Introduction Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD. Methods We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline. Results During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure). Conclusions The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.
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              Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction.

              Evandro Fei Fang, Morten Scheibye-Knudsen, Lear Brace … (2014)
              Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA-deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD(+)-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition or by supplementation with NAD(+) precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a nuclear-mitochondrial crosstalk that is critical for the maintenance of mitochondrial health. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (iso-abbrev): Nucleic Acids Res
                Journal ID (hwp): nar
                Journal ID (publisher-id): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date (Print): 30 January 2015
                Publication date (Electronic): 30 December 2014
                Publication date PMC-release: 30 December 2014
                Volume: 43
                Issue: 2
                Pages: 943-959
                Affiliations
                [1 ]Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA
                [2 ]Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA
                [3 ]Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo-Ribeirao Preto, SP 14049-900, Brazil
                [4 ]Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA
                [5 ]Laboratory of Genetics, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: vbohr@ 123456nih.gov
                Article
                DOI: 10.1093/nar/gku1356
                PMC ID: 4333403
                PubMed ID: 25552414
                SO-VID: b25d9100-f48e-41c2-a274-59874e566158
                Copyright © Published by Oxford University Press on behalf of Nucleic Acids Research 2014. This work is written by US Government employees and is in the public domain in the US
                History
                Date accepted : 16 December 2014
                Date revision received : 15 December 2014
                Date received : 03 November 2014
                Page count
                Pages: 17
                Categories
                Subject: Genome Integrity, Repair and Replication
                Custom metadata
                cover-date 30 January 2015

                ScienceOpen disciplines: Genetics
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                ScienceOpen disciplines: Genetics

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