Numerous lines of evidence suggest that DNA damage contributes to the initiation, progression, and severity of neurodegenerative diseases. However, the molecular mechanisms responsible for this relationship remain unclear. This review integrates historical data with contemporary findings to propose that DNA damage exacerbates neurodegenerative diseases by inducing transcription errors.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2023
Alzheimer's disease (AD) is characterized by toxic protein accumulation in the brain. Ubiquitination is essential for protein clearance in cells, making altered ubiquitin signaling crucial in AD development. A defective variant, ubiquitin B + 1 (UBB), created by a non-hereditary RNA frameshift mutation, is found in all AD patient brains post-mortem.
View Article and Find Full Text PDFTo determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others.
View Article and Find Full Text PDFSpinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by loss of motor neurons (MN) in the spinal cord leading to progressive muscle atrophy and weakness. SMA is caused by mutations in the survival motor neuron 1 () gene, resulting in reduced levels of survival motor neuron (SMN) protein. The mechanisms that link SMN deficiency to selective motor neuron dysfunction in SMA remain largely unknown.
View Article and Find Full Text PDFKii amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder that is endemic to the Kii peninsula of Japan. The disorder is clinically characterized by a variable combination of parkinsonism, dementia, and motor neuron symptoms. Despite extensive investigations, the etiology and pathogenesis of ALS/PDC remain unclear.
View Article and Find Full Text PDFActa Neuropathol
September 2020
In the original article, the panels "Brain organoids" and "Transgenics" were included in Fig. 5 without permission.
View Article and Find Full Text PDFLong non-coding RNAs (lncRNAs) are a diverse class of transcripts that are >200 nucleotides long and lack significant protein-coding potential. LncRNAs are emerging as major regulators of gene expression networks in various physiological and pathological processes. Interestingly, many lncRNAs show tissue-specific expression, for example, in the nervous system.
View Article and Find Full Text PDFNeuronal development is a complex multistep process that shapes neurons by progressing though several typical stages, including axon outgrowth, dendrite formation, and synaptogenesis. Knowledge of the mechanisms of neuronal development is mostly derived from the study of animal models. Advances in stem cell technology now enable us to generate neurons from human induced pluripotent stem cells (iPSCs).
View Article and Find Full Text PDFFront Mol Neurosci
November 2019
The brain is a genomic mosaic. Cell-to-cell genomic differences, which are the result of somatic mutations during development and aging, contribute to cellular diversity in the nervous system. This genomic diversity has important implications for nervous system development, function, and disease.
View Article and Find Full Text PDFAmyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD.
View Article and Find Full Text PDFThe nervous system is composed of a large variety of neurons with a diverse array of morphological and functional properties. This heterogeneity is essential for the construction and maintenance of a distinct set of neural networks with unique characteristics. Accumulating evidence now indicates that neurons do not only differ at a functional level, but also at the genomic level.
View Article and Find Full Text PDFGuam parkinsonism-dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss.
View Article and Find Full Text PDFThe accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP 43). Using a yeast model for TDP 43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP 43.
View Article and Find Full Text PDFTDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways.
View Article and Find Full Text PDFCytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis.
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