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| Status |
Public on Feb 26, 2020 |
| Title |
Senataxin, the helicase mutated in AOA2 and ALS4, plays a role in autophagy regulation [microarray] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Senataxin (SETX) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response, through resolution of R-loop structures. Mutations in SETX result in either of two distinct neurodegenerative disorders. SETX dominant mutations result in a juvenile form of ALS (amyotrophic lateral sclerosis) named ALS4, while recessive mutations are responsible for an ataxia called AOA2 (ataxia with oculomotor apraxia type 2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expression changes following SETX depletion. We observed effects on both transcription and RNA processing, but surprisingly observed decreased R-loop accumulation in SETX depleted cells. Importantly, we discovered a strong connection between SETX and the autophagy pathway, reflecting a direct effect on the transcription of autophagy genes. We show that SETX depletion inhibits the progression of autophagy, leading to an accumulation of ubiquitinated proteins, decreased ability to clear protein aggregates, as well as mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed a perturbation of the autophagy pathway. Our work has thus identified a novel function for SETX in the regulation of autophagy, whose modulation may have a therapeutic impact for AOA2.
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| Overall design |
U87 cells treated with SETX siRNA or control siRNA in triplicates
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| Contributor(s) |
Li W, Hoque M, Richard P, Feng S, Tsai Y, Muhith U, Irizarry-Cole J, Stolz K, Manley JL, Tian B |
| Citation missing |
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| Submission date |
Feb 21, 2020 |
| Last update date |
Mar 01, 2020 |
| Contact name |
Wencheng Li |
| Organization name |
PTC Therapeutics
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| Street address |
100 Corporate Count
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| City |
South Plainfield |
| State/province |
NJ - New Jersey |
| ZIP/Postal code |
07080 |
| Country |
USA |
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| Platforms (1) |
| GPL5175 |
[HuEx-1_0-st] Affymetrix Human Exon 1.0 ST Array [transcript (gene) version] |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE145677 |
Senataxin, the helicase mutated in AOA2 and ALS4, plays a role in autophagy regulation |
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| Relations |
| BioProject |
PRJNA607938 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE145676_RAW.tar |
139.2 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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