MR evidence of structural and metabolic changes in brains of patients with Werner?s syndrome

Stefano, Nicola De; Dotti, Maria Teresa; Battisti, Carla; Sicurelli, Francesco; Stromillo, Maria Laura; Mortilla, M.; Federico, Antonio

doi:10.1007/s00415-003-0167-4

Cited by 10 publications

(6 citation statements)

References 23 publications

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“…The resultant neuropathology in these syndromes is not well characterized, although the syndromes produce quite dramatic and varying phenotypes outside of the nervous system, including cancer, progeria and proportional body size defects. In the case of WS, a neurological involvement has been reported but is controversial162-164. Why mutations in these helicases don't more substantially impact the nervous system is not clear.…”

Section: [8] Other Disorders Related To Dna Repair Deficitsmentioning

confidence: 99%

DNA repair deficiency and neurological disease

2009

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PrefaceResponding to genotoxic stress is a prerequisite for development of the nervous system. Mutations in a variety of DNA repair factors can lead to human diseases that are characterized by pronounced neuropathology. In many of these syndromes the neurological component is amongst the most deleterious aspects of the disease. The nervous system poses a particular challenge in terms of clinical intervention, as the neuropathology often arises during nervous system development, and can be fully penetrant by childhood. Understanding how DNA repair deficiency impacts the nervous system will provide a rationale basis for therapies targeted at ameliorating the neurological problems in these syndromes. [1] IntroductionMaintaining genomic integrity by DNA repair is fundamental to the function and survival of an organism. Compromising genomic DNA can lead to a spectrum of human disorders that exhibit developmental defects, immune deficiency and cancer. In particular, the nervous system is often profoundly affected by DNA repair deficiency, which can result in neurodegeneration, microcephaly or brain tumors. More broadly, defective DNA repair in mature neural tissues has also been linked to aging and recently to common neurodegenerative syndromes such as Alzheimer's disease and Parkinson disease [1][2][3][4] .The developmental dynamics of the nervous system requires vigilant DNA repair processes capable of repairing multiple types of damage. DNA repair is especially critical during the early period of rapid proliferation as progenitors expand and differentiate to generate the nervous system. In the mature nervous system, DNA repair is also essential to prevent DNA damage, arising from sources such as oxidative metabolism, from blocking active transcription. Understanding the interplay between signaling networks that function to maintain genomic stability in the nervous system will be of paramount importance for the Resources NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript treatment of diseases associated with DNA repair deficiency. This review will discuss the role of DNA repair during the genesis of the nervous system, and how this process maintains neural homeostasis.[2] The importance of DNA integrity during neural developmentMany human DNA repair syndromes are congenital and so it is clear that the developing nervous system can be markedly affected by DNA repair deficiency. Therefore, understanding neural development is important for determining how DNA repair deficiency impacts the nervous system. Detailed reviews that summarize neural development are available [5][6][7][8][9] . In humans, the nervous system begins to form during the first trimester of gestation and continues until after birth. The complexity of the mature nervous system results from a relatively simple strategy of proliferation, differentiation and migration (Fig. 1). The engine driving neural development is rapid cellular proliferation within the ventricular and subventricular zones that line the four ventricles presen...

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Section: [8] Other Disorders Related To Dna Repair Deficitsmentioning

confidence: 99%

DNA repair deficiency and neurological disease

2009

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“…46 EFEMP1 was originally cloned from senescent fibroblasts derived from a patient with Werner syndrome a disease of premature aging with diffuse structural abnormalities in the brain white matter. 47, 48 …”

Section: Discussionmentioning

confidence: 99%

Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Verhaaren¹,

Debette²,

Bis³

et al. 2015

Circ Cardiovasc Genet

160

187

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Background The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multi-ethnic genome-wide association studies. Methods and Results We included 21,079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (N=17,936), African (N=1,943), Hispanic (N=795), and Asian (N=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each SNP and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (p=2.7×10−19) and identified novel loci on chr10q24 (p=1.6×10−9) and chr2p21 (p=4.4×10−8). In the multi-ethnic meta-analysis, we identified two additional loci, on chr1q22 (p=2.0×10−8) and chr2p16 (p=1.5×10−8). The novel loci contained genes that have been implicated in Alzheimer’s disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16). Conclusions We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms.

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“…Although neurodegenerative disease is not a major phenotype associated with WS, there are a number of studies reporting neurological pathologies associated with several WS patients. [63][64][65] Thus, the GSEA and the Ingenuity Pathway analysis (IPA) are two independent tools for data integration and visualization that provided converging results. They complemented each other and delivered a more detailed view of the biologial network affected by a WRN knock down.…”

Section: Methodsmentioning

confidence: 99%

The Werner syndrome protein affects the expression of genes involved in adipogenesis and inflammation in addition to cell cycle and DNA damage responses

Turaga¹,

Paquet²,

Sild³

et al. 2009

Cell Cycle

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Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies. The protein deficient in WS (WRN) is a RecQ-type DNA helicase involved in DNA repair, replication, telomere maintenance and transcription. However, precisely how WRN deficiency leads to the numerous WS pathologies is still unknown. Here we use short-term siRNA-based inhibition of WRN to test the direct consequences of its loss on gene expression. Importantly, this short-term knock down of WRN protein level was sufficient to trigger an expression profile resembling fibroblasts established from old donor patients. In addition, this treatment altered sets of genes involved in 14 distinct biological pathways. Besides the already known impact of WRN on DNA replication, DNA repair, the p21/p53 pathway, and cell cycle, gene set enrichment analyses of our microarray data also uncover significant impact on the MYC, E2F, cellular E2A and ETV5 transcription factor pathways as well as adipocyte differentiation, HIF1, NFkappaB and IL-6 pathways. Finally, short-term siRNA-based inhibition of mouse Wrn expression in the pre-adipocyte cell line 3T3-L1 confirmed the impact of WRN on adipogenesis. These results are consistent with the pro-inflammatory status and lipid abnormalities observed in WS patients. This approach thus identified new effectors of WRN activity that might contribute to the WS phenotype.

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MR evidence of structural and metabolic changes in brains of patients with Werner?s syndrome

Abstract: Our findings suggest that, despite normal appearance on conventional MRI, diffuse structural and metabolic tissue damage can be demonstrated in WS brains by means of sensitive MR methods even in patients with moderate or subclinical CNS involvement.

Cited by 10 publications

References 23 publications

DNA repair deficiency and neurological disease

DNA repair deficiency and neurological disease

Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

The Werner syndrome protein affects the expression of genes involved in adipogenesis and inflammation in addition to cell cycle and DNA damage responses

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