PXD014163

PXD014163 is an original dataset announced via ProteomeXchange.

Title	ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ
Description	Recently, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). CCNF encodes for cyclin F, a substrate recognition component of an E3-ubiquitin ligase. Mutations in CCNF directly implicates disruption in the ubiquitin-proteasome system in the pathogenesis of ALS/FTD. In this study we used an unbiased proteomic screening workflow using the proximity-based ligation method, BioID, to identify putative interaction partners of cyclin F. In doing so, we found over 100 putative interaction partners of cyclin F. Notably, we demonstrated that cyclin F closely associates with a number of essential paraspeckle proteins, which are stress-responsive proteins that have recently been implicated in ALS pathogenesis. We further demonstrate that SCFcyclin F mediates the direct ubiquitylation and subsequent proteasomal degradation of RBM14, a core component of the paraspeckle complex. This degradation is defective when cyclin F carries an ALS/FTD-causing mutation, leading to RBM14 accumulation in primary neurons upon proteasome inhibition. Additionally, analysis of ALS patient post-mortem tissue revealed that RBM14 levels were significantly reduced in post-mortem ALS patient motor cortex and significantly reduced in the neurons of spinal cord tissue. Together, our data indicate that defects in RBM14 homeostasis, which can be due to defects in cyclin F-mediated degradation, may be a common factor underlying ALS/FTD disease pathogenesis.
HostingRepository	PRIDE
AnnounceDate	2021-03-18
AnnouncementXML	Submission_2021-03-18_01:19:43.277.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD014163
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Albert Lee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; Acetyl; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-06-06 08:59:33	ID requested
1	2021-03-18 00:21:58	announced
⏵ 2	2021-03-18 01:19:44	announced	2021-03-18: Updated project metadata.

Rayner SL, Cheng F, Hogan AL, Grima N, Yang S, Ke YD, Au CG, Morsch M, De Luca A, Davidson JM, Molloy MP, Shi B, Ittner LM, Blair I, Chung RS, Lee A, ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ. Hum Mol Genet, 30(11):971-984(2021) [pubmed]

submitter keyword: BioID, ubiquitylation, proteomics, amyotrophic lateral sclerosis, frontotemporal dementia, paraspeckles, cyclin F, RBM14, homeostasis

Albert Lee
contact affiliation	Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, NSW 2109
contact email	albert.lee@mq.edu.au
lab head
Albert Lee
contact affiliation	Macquarie University
contact email	albert.lee@mq.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014163
     1. Label: PRIDE project
     2. Name: ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ