Review: Somatic mutations in neurodegeneration

Leija‐Salazar, Melissa; Piette, Caitlin E.; Proukakis, Christos

doi:10.1111/nan.12465

Cited by 75 publications

(59 citation statements)

References 169 publications

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“…More generally, recent findings show that the retrovirus-like Gag protein Arc1 binds RNA and traffics across synaptic buttons, suggesting the possibility of wide transfer of mutated disease driving RNAs [63]. The discovery of somatic mutations in genes causing familial, amyloid-driven AD [64][65][66] also in our cohorts (DLPFC , Table S5, Fig. S7) provides increased relevance to our findings.…”

Section: Discussionsupporting

confidence: 72%

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

et al. 2019

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With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi. RNA-Seq of olfactory bulbs also identified a novel ADNP hotspot mutation, c.2187_2188insA. Altogether, 665 mutations in 596 genes with 441 mutations in AD patients (389 genes, 38% AD-exclusive mutations) and 104 genes presenting disease-causing mutations (OMIM) were discovered. OMIM AD mutated genes converged on cytoskeletal mechanisms, autism and ID causing mutations (about 40% each). The number and average frequencies of AD-related mutations per subject were higher in AD subjects compared to controls. RNA-seq datamining (hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus-583 subjects) yielded similar results. Overlapping all tested brain areas identified unique and shared mutations, with ADNP singled out as a gene associated with autism/ID/AD and presenting several unique aging/AD mutations. The large fusiform gyrus library (117 subjects) with high sequencing coverage correlated the c.2187_2188insA ADNP mutation frequency to Braak stage (tauopathy) and showed more ADNP mutations in AD specimens. In cell cultures, the ADNP-derived snippet NAP inhibited mutated-ADNP-microtubule (MT) toxicity and enhanced Tau-MT association. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.

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Section: Discussionsupporting

confidence: 72%

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

et al. 2019

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“…Fig. 4a), supporting the hypothesis that somatic mutation load could contribute to the increasing risk of neurodegenerative diseases with age 24 .…”

Section: Introductionsupporting

confidence: 81%

“…It has been proposed that somatic mutations contribute to aging and organ deterioration 40 ; consistent with this, we observed a positive correlation between age and mutation burden in most tissues. Interestingly, several brain regions are among the tissues exhibiting stronger age correlation, and somatic mutations have been shown to have a role in neurodegeneration 24 .…”

Section: Discussionmentioning

confidence: 99%

The somatic mutation landscape of the human body

García-Nieto

Morrison

Fraser

2019

Preprint

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Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet remain largely uncharacterized. To gain a better understanding of their distribution and functional impacts, we leveraged the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7,500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, revealed a wide diversity of tissuespecific mutation profiles associated with gene expression levels and chromatin states. We found pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which were under positive selection and were highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis. RESULTS Somatic mutation calling across 36 non-disease tissues from 547 peopleOur method considers genomic positions where we observed two alleles in the RNA-seq reads and assesses whether they are likely to be bona fide DNA somatic mutations (Fig 1a). We optimized the minimum levels of RNA-seq read depth, sequence quality, and number of reads supporting the variant allele to limit the impact of sequencing errors (Supp. Fig. 1a; see Methods). We then applied extensive filters to eliminate false-positives from biological and technical sources, including RNA editing, sequencing errors, and mapping errors (see Methods ; Fig 1b- Fig. 2a; Supp. Table 1).To validate the method, we compared somatic mutation calls from 105 blood RNA-seq samples to exome DNA sequencing performed on the same samples 23 (Fig. 1d). We observed a false-discovery rate (FDR) of 29% which represents the percentage of somatic mutations called from RNA-seq not having evidence in the corresponding DNA exome-seq sample (Fig. 1d, Supp. Fig. 1c; see methods). This is comparable to the 40% FDR in a previous study that inferred mutations from scRNA-seq in pancreas 22 .After applying the pipeline and filters to RNA-seq data from the GTEx project, we retained a total of 7,584 samples from 36 different tissues and 547 different individuals with no detectable cancer (Supp. Table 2). This resulted in a total of 280,843 unique mutations (Supp. Table 3), most of which were rare across the entire data set (median frequency = 0.026% of samples; Supp. Fig. 2b).We first investigated the factors influencing mutation counts per sample and tissue (see Methods). The main contributor was sequencing depth and to a lesser extent other biological and technical factors (Supp. Fig. 2c, Supp. Table 4). Tissues that have more mutations than expected from sequencing depth include those most often exposed to environmental mutagens or with a high cellular turnover like skin, lung, blood, esophagus mucosa, spleen, liver and small intestine ( Fig. 2a). On the other end of the spectrum are those with low environmental exposure or low cellular turnover such as brain, adre...

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“…These mutations could impair neuronal health and function in largely undefined ways. Interestingly, somatic mutations or variants in brain neurons with low allele frequency has been associated with aging and neurodegenerative diseases [125][126][127]. This somatic mosaicism has, in particular, been demonstrated in AD brains.…”

Section: Dna Damage and Somatic Mutationsmentioning

confidence: 99%

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

Tang

2020

Toxics

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Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.

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Review: Somatic mutations in neurodegeneration

Cited by 75 publications

References 169 publications

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

The somatic mutation landscape of the human body

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

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