Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies

Autor: Nancy M. Bonini, John Q. Trojanowski, Ashley Sartoris, Virginia M.-Y. Lee, Amit Berson, Charlton G. Otte, Lindsey D. Goodman, James A. Aykit
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
lcsh:RC346-429
0302 clinical medicine
C9orf72
Drosophila Proteins
Amyotrophic lateral sclerosis
Ref1
Ataxin-2
Motor Neurons
Gene knockdown
Neurodegeneration
Nuclear Proteins
RNA-Binding Proteins
Up-Regulation
3. Good health
Cell biology
DNA-Binding Proteins
Frontotemporal Dementia
Nuclear transport
Drosophila
Female
Frontotemporal dementia
mRNA
Transgene
Down-Regulation
Biology
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Downregulation and upregulation
mental disorders
medicine
Animals
Humans
Amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)
RNA
Messenger
lcsh:Neurology. Diseases of the nervous system
Research
Amyotrophic Lateral Sclerosis
TAR DNA-binding protein 43 (TDP-43) (TARDBP)
medicine.disease
030104 developmental biology
Gene Expression Regulation
ALYREF
Neurology (clinical)
Trinucleotide repeat expansion
030217 neurology & neurosurgery
Transcription Factors
Zdroj: Acta Neuropathologica Communications
Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-10 (2019)
ISSN: 2051-5960
DOI: 10.1186/s40478-019-0710-x
Popis: RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in Drosophila for RBPs that genetically interact with TDP-43, we found that downregulation of the mRNA export factor Ref1 (fly orthologue to human ALYREF) mitigated TDP-43 induced toxicity. Further, Ref1 depletion also reduced toxicity caused by expression of the C9orf72 GGGGCC repeat expansion. Ref1 knockdown lowered the mRNA levels for these related disease genes and reduced the encoded proteins with no effect on a wild-type Tau disease transgene or a control transgene. Interestingly, expression of TDP-43 or the GGGGCC repeat expansion increased endogenous Ref1 mRNA levels in the fly brain. Further, the human orthologue ALYREF was upregulated by immunohistochemistry in ALS motor neurons, with the strongest upregulation occurring in ALS cases harboring the GGGGCC expansion in C9orf72. These data support ALYREF as a contributor to ALS/FTD and highlight its downregulation as a potential therapeutic target that may affect co-existing disease etiologies. Electronic supplementary material The online version of this article (10.1186/s40478-019-0710-x) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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