Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 40, Pages 14524-14529Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1405741111
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Funding
- National Institute of Neurological Disorders and Stroke [NS050641, NS078504, NS070142, NS081474, NS064091, NS009904, NS078287, AG13854]
- National Institute on Aging [AG20506]
- Les Turner ALS Foundation
- Vena E. Schaff ALS Research Fund, a Harold Post Research Professorship
- Herbert and Florence C. Wenske Foundation
- David C. Asselin MD Memorial Fund
- Help America Foundation
- George Link, Jr. Foundation
- Les Turner ALS Foundation/Herbert C. Wenske Foundation
- National Cancer Institute (NCI) [CA060553]
- NCI [CA060553]
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Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2(P497H) transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including Ub(G76V)-GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.
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