Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases

Mills, James D.; Janitz, Michael

doi:10.1016/j.neurobiolaging.2011.10.030

Cited by 95 publications

(72 citation statements)

References 137 publications

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“…Though alternative splicing of specific genes has been previously reported (39), global disruption of RNA processing has never been suggested in AD. To address this possibility, we performed deep RNA sequencing (40) of frontal cortex RNAs using two independent sample groups from the brain banks of Emory University (four control and five AD cases) and the University of Kentucky (UKY; three control and three AD cases).…”

Section: Resultsmentioning

confidence: 99%

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Bai

Hales

Chen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

287

380

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Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer's disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc boxdependent-interacting protein 1, clusterin, and presenilin-1. U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein.Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.proteomics | liquid chromatography-tandem mass spectrometry | U1A | RNA-seq | premature cleavage and polyadenylation

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Section: Resultsmentioning

confidence: 99%

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Bai

Hales

Chen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

287

380

View full text Add to dashboard Cite

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“…Furthermore, since regulatory and signaling elements in disordered regions can be comprised of just a few more or less continuous amino acids, and since a high density of functionally important segments can be located within disordered regions, functionality of IDPs can be completely rewired via AS. 266,267 AS is known to occur in almost all human genes, and therefore alterations of this process are intimately connected to the pathogenesis of various human diseases, ranging from cancer, 268,269 to neurodegenerative [270][271][272] and cardiovascular diseases. 273 Many of the pathology-related proteins affected by pathology-related AS are intrinsically disordered.…”

Section: Alternative Splicing In Idp Function and Dysfunctionmentioning

confidence: 99%

Introducing Protein Intrinsic Disorder

et al. 2014

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“…Changes in AS have been shown to have important roles in many human neurological developmental processes, including neuronal cell migration, synapse formation and establishing neurotransmitter receptors (Grabowski, 2011). Failure or dysregulation of AS can cause abnormal neural development and neuropathology and has been associated with a number of neurodegenerative and psychiatric disorders (Mills and Janitz, 2012). See also: Alternative Splicing and Human Disease Some AS patterns have been shown to be modulated in response to external stimuli, such as depolarisation of neurons or activation of signal transduction cascades (Li et al, 2007), and AS patterns of numerous neuronally expressed genes have been found to be modified following stress insults.…”

Section: Asmentioning

confidence: 99%

Behavioural Genetics in the Postgenomics Era

Charney

2014

Encyclopedia of Life Sciences

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There is growing evidence that the complexity of higher organisms does not correlate with the ‘complexity’ of the genome (the human genome contains fewer protein coding genes than corn, and many genes are preserved across species). Rather, complexity is associated with the complexity of the pathways and processes whereby the cell utilises the deoxyribonucleic acid molecule, and much else, in the process of phenotype formation. These processes include the activity of the epigenome, noncoding ribonucleic acids , alternative splicing and post‐translational modifications. Not accidentally, all of these processes appear to be of particular importance for the human brain, the most complex organ in nature. Because these processes can be highly environmentally reactive, they are a key to understanding behavioural plasticity and highlight the importance of the developmental process in explaining behavioural outcomes. Key Concepts: Humans possess fewer protein‐coding genes than maize (i.e. corn) and about the same number as a nematode. There is now strong evidence that the complexity of higher organisms correlates with the relative amount of noncoding RNA rather than the number of protein‐coding genes. Epigenetic processes are key to every aspect of human development from cellular differentiation to learning and memory. Epigenetic mechanisms provide an explanation on the molecular level as to how the pre‐ and postnatal environments can impact offspring's behaviour. Alternative splicing is one mechanism that enables the human body to create over 100 000 proteins with a genome that contains only 20 000 protein coding genes. Each gene in the human genome is not ‘encoded’ for the production of a single protein. Isoforms can have very different and even antithetical physiological effects. Alternative splicing patterns are modulated in response to external stimuli, such as depolarisation of neurons, activation of signal transduction cascades and stress. Post‐translational modification supplements alternative splicing as a means of creating protein diversity with a limited number of protein coding genes. DNA is not the sole biological agent of inheritance.

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Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases

Cited by 95 publications

References 137 publications

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Introducing Protein Intrinsic Disorder

Behavioural Genetics in the Postgenomics Era

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