Faulty splicing and cytoskeleton abnormalities in H untington's disease
Open accessAbstract
Huntington's disease (HD) is caused by a CAG‐repeat encoding a polyglutamine (polyQ) tract in the huntingtin protein. There is plenty of evidence of polyQ‐driven toxicity. However, CAG repeat RNA‐driven alteration of splicing has recently been proposed in analogy to CUG‐repeat diseases. Here we review the reported alteration of the CAG‐repeat associated splicing factor SRSF6 in brains of HD patients and mouse models and how this correlates with altered splicing of, at least, two microtubule‐associated proteins in HD, namely MAPT (tau) and MAP2. Regarding tau, altered splicing of exon 10 has been reported, along with increased levels and 4R/3R‐tau ratio and detection of tau in a new nuclear rod‐shaped histopathological hallmark termed tau nuclear rod (TNR) or tau nuclear indentation (TNI). These findings, together with an attenuation of HD phenotype in R6/1 mice with tau deficiency and subsequent studies showing increased phosphorylation in mouse models and increased levels in CSF of patients, has led to proposing HD as a tauopathy. Regarding MAP2, an increase in its juvenile form and a decrease in total MAP2 together with redistribution from dendrites to soma is observed in HD patients, which may contribute to the dendritic atrophy in HD. Furthermore, MAP2 positive structures filling nuclear indentations have occasionally been found and co‐localized with tau. Therefore, altered MAP function with imbalance in tau/MAP2 content could contribute to HD striatal atrophy and dysfunction. Besides, TNIs might be indicative of such MAP abnormalities. TNIs are also found in early pathology Alzheimer's disease and in tauopathy mice over‐expressing mutant 4R‐tau. This indicates that tau alteration is sufficient for TNI detection, which becomes a marker of increased total tau and/or altered 4R/3R‐tau ratio and reporter of pathology‐associated nuclear indentations. Altogether, these recent studies suggest that correcting the SRSF6‐driven missplicing and/or microtubule‐associated imbalance might be of therapeutic value in HD.
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Aberrant splicing in Huntington's disease raises total tau and juvenile MAP2; MAP2 withdraws from dendrites toward the cell body in patients, and together these changes promote dendritic and striatal atrophy.
“faulty splicing in Huntington's disease increases total tau and the juvenile form of MAP2”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Fernandez-Nogales et al., 2016
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Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Crapser, J. D., Ochaba, J., Soni, N., Reidling, J. C., Thompson, L. M., & Green, K. N. (2020) · Brain · doi:10.1093/brain/awz363 · Cited by 157 · see citing works
- Authors
- Fernández‐Nogales, M., Santos‐Galindo, M., Hernández, I. H., Cabrera, J. R., & Lucas, J. J.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Dartmouth College (US)
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2016-11
- Volume
- 26
- Issue
- 6
- Pages
- 772-778
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC8028924
- OpenAlex
- W2511889916
- Cited by
- 41
- References
- 64
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 1 · 2016: 1
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-PI2015-2/06-3)
- Spanish Ministery of Economy and Competitiveness (MINECO, SAF2015-65371-R)
- Fundación BBVA
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- Huntington's disease, CAG repeat expansion, polyglutamine toxicity, SRSF6, tau protein, MAP2, tauopathy, microtubule-associated proteins, dendritic atrophy, striatal atrophy, tau phosphorylation, R6/1 mice, Alzheimer's disease
- MeSH terms
- Serine-Arginine Splicing Factors, Huntingtin Protein, RNA Splicing Factors, Animals, Brain, Cytoskeleton, Disease Models, Animal, Humans, Huntington Disease, Microtubule-Associated Proteins, Neurons, Phosphoproteins, tau Proteins, Alternative Splicing, Trinucleotide Repeat Expansion
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