期刊
MOLECULAR NEURODEGENERATION
卷 13, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13024-018-0288-y
关键词
Frontotemporal dementia; Amyotrophic lateral sclerosis; TDP-43; Progranulin
资金
- ALS Therapy Alliance
- Opening the Future Fund (KU Leuven)
- Fund for Scientific Research Flanders (FWO-Flanders)
- Interuniversity Attraction Poles (IUAP) program of the Belgian Federal Science Policy Office [P7/16]
- ALS Liga Belgium
- Een hart voor ALS
- Laeversfonds voor ALS-onderzoek
- Alzheimer Research Foundation (SAO-FRA)
- Flemish Government
- European Union Joint Programme-Neurodegenerative Disease Research (JPND) project RiMod-FTD
BackgroundTAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of similar to 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43-induced neurodegeneration is not yet clear.MethodsWe studied the effect of PGRN on the neurodegenerative phenotype in TDP-43(A315T) mice.ResultsPGRN reduced the levels of insoluble TDP-43 and histology of the spinal cord revealed a protective effect of PGRN on the loss of large axon fibers in the lateral horn, the most severely affected fiber pool in this mouse model. Overexpression of PGRN significantly slowed down disease progression, extending the median survival by approximately 130days. A transcriptome analysis did not point towards a single pathway affected by PGRN, but rather towards a pleiotropic effect on different pathways.ConclusionOur findings reveal an important role of PGRN in attenuating mutant TDP-43-induced neurodegeneration.
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