The Genetics of<i>C9orf72</i>Expansions

Gijselinck, Ilse; Cruts, Marc; Broeckhoven, Christine Van

doi:10.1101/cshperspect.a026757

Cited by 29 publications

(15 citation statements)

References 147 publications

(210 reference statements)

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“…Furthermore, it is critical to note that protein abnormalities that define neurodegenerative diseases can be present before the onset of clinical features (Gibb and Lees 1988;Sparks et al 1994;Schmitt et al 2000;Adler et al 2010;Evidente et al 2011;Frigerio et al 2011;Milenkovic and Kovacs 2013;Dugger et al 2014c) and more than one neurodegenerative disease process can be found in an individual (Uchikado et al 2006a;Dugger et al 2014a). At present, diagnostic biomarkers are not available, except in rare cases in which a causative genetic mutation can be shown to cause the disorder (Ghasemi and Brown 2016;Gijselinck et al 2016;Hinz and Geschwind 2016;TCWand Goate 2016). Hence, specific in vivo biomarkers, including biofluid Amyloidoses Creutzfeldt -Jakob disease (genetic, variant, sporadic, iatrogenic) and molecular imaging markers (some highlighted in Kolb and Andres 2016;Seeley 2016), are a major research priority.…”

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confidence: 99%

Pathology of Neurodegenerative Diseases

Dugger

Dickson

2017

Cold Spring Harb Perspect Biol

1,156

702

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Neurodegenerative disorders are characterized by progressive loss of selectively vulnerable populations of neurons, which contrasts with select static neuronal loss because of metabolic or toxic disorders. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormality. The most common neurodegenerative disorders are amyloidoses, tauopathies, α-synucleinopathies, and TDP-43 proteinopathies. The protein abnormalities in these disorders have abnormal conformational properties. Growing experimental evidence suggests that abnormal protein conformers may spread from cell to cell along anatomically connected pathways, which may in part explain the specific anatomical patterns observed at autopsy. In this review, we detail the human pathology of select neurodegenerative disorders, focusing on their main protein aggregates.

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mentioning

confidence: 99%

Pathology of Neurodegenerative Diseases

Dugger

Dickson

2017

Cold Spring Harb Perspect Biol

1,156

702

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“…The repeat expansion mutation in C9orf72 , located on chromosome 9, is a major causal factor in the pathogenesis of both FTLD and ALS, forming a disease spectrum (Gijselinck et al, 2016). The hexanucleotide repeat of G 4 C 2 is expanded in patients and is generally considered to be pathological when the expansion contains ≥ 2–24 repeat units (Renton et al, 2011; Gijselinck et al, 2012, 2018; Van Mossevelde et al, 2018). The exact mechanism of disease is unclear so far.…”

Section: Genetic Screening For Known Causal Genes For Ftdmentioning

confidence: 99%

The Use of Biomarkers and Genetic Screening to Diagnose Frontotemporal Dementia: Evidence and Clinical Implications

2019

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Within the wide range of neurodegenerative brain diseases, the differential diagnosis of frontotemporal dementia (FTD) frequently poses a challenge. Often, signs and symptoms are not characteristic of the disease and may instead reflect atypical presentations. Consequently, the use of disease biomarkers is of importance to correctly identify the patients. Here, we describe how neuropsychological characteristics, neuroimaging and neurochemical biomarkers and screening for causal gene mutations can be used to differentiate FTD from other neurodegenerative diseases as well as to distinguish between FTD subtypes. Summarizing current evidence, we propose a stepwise approach in the diagnostic evaluation. Clinical consensus criteria that take into account a full neuropsychological examination have relatively good accuracy (sensitivity [se] 75–95%, specificity [sp] 82–95%) to diagnose FTD, although misdiagnosis (mostly AD) is common. Structural brain MRI (se 70–94%, sp 89–99%) and FDG PET (se 47–90%, sp 68–98%) or SPECT (se 36–100%, sp 41–100%) brain scans greatly increase diagnostic accuracy, showing greater involvement of frontal and anterior temporal lobes, with sparing of hippocampi and medial temporal lobes. If these results are inconclusive, we suggest detecting amyloid and tau cerebrospinal fluid (CSF) biomarkers that can indicate the presence of AD with good accuracy (se 74–100%, sp 82–97%). The use of P-tau 181 and the Aβ 1 – 42 /Aβ 1 – 40 ratio significantly increases the accuracy of correctly identifying FTD vs. AD. Alternatively, an amyloid brain PET scan can be performed to differentiate FTD from AD. When autosomal dominant inheritance is suspected, or in early onset dementia, mutation screening of causal genes is indicated and may also be offered to at-risk family members. We have summarized genotype–phenotype correlations for several genes that are known to cause familial frontotemporal lobar degeneration, which is the neuropathological substrate of FTD. The genes most commonly associated with this disease ( C9orf72, MAPT, GRN, TBK1 ) are discussed, as well as some less frequent ones ( CHMP2B, VCP ). Several other techniques, such as diffusion tensor imaging, tau PET imaging and measuring serum neurofilament levels, show promise for future implementation as diagnostic biomarkers.

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“…Other neuropathological disorders markedly linked to nuclear transport alterations are FTD and ALS (Gijselinck, Cruts, & Broeckhoven, ). The repeat expansion of the hexanucleotide GGGGCC (G4C2) in a noncoding region of the C9orf72 gene is the most common cause of sporadic and familial form of these disorders, but the molecular mechanisms of neurodegeneration are quite unknown.…”

Section: Protein Aggregates Affect Nucleocytoplasmic Transport Duringmentioning

confidence: 99%

Nucleus–cytoplasm cross‐talk in the aging brain

Benvegnù

2019

J of Neuroscience Research

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Aging is a primary risk factor for fatal neurodegenerative disorders, yet the mechanisms underlying physiological healthy aging and pathological aging, and how these mechanisms can divert one scenario to the other, are not completely understood. In recent years, reports indicate that alterations in nucleocytoplasmic transport may be a hallmark of both healthy and pathological aging. In this review, I summarize recent evidence supporting this information, specifically focusing on the association between the nucleocytoplasmic transport and aging of the brain, indicating both common and case‐specific mechanisms and their interplay, and pointing out alterations of these mechanisms as regulatory “switches” for the fate of the aging brain. Importantly, some of these alterations are intervenable druggable targets, paving the way to a future pharmacotherapeutic intervention.

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The Genetics ofC9orf72Expansions

Cited by 29 publications

References 147 publications

Pathology of Neurodegenerative Diseases

Pathology of Neurodegenerative Diseases

The Use of Biomarkers and Genetic Screening to Diagnose Frontotemporal Dementia: Evidence and Clinical Implications

Nucleus–cytoplasm cross‐talk in the aging brain

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