PXD064648

PXD064648 is an original dataset announced via ProteomeXchange.

Title	ALS-FTD-linked CCNFS621G Drives Increased Astrocyte Ramification, Alterations in the Proteome Related to Translation, Mitochondrial Function and Neuroinflammation, and Reduced Motor Neuron Excitability
Description	Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with interlinked pathophysiology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause either ALS or FTD or both, within the same family. The majority of previous published research on CCNFS621G in ALS/FTD has used overexpression of exogenous Cyclin F, and as a result may have encountered artefacts of pathology caused by dysregulation of native or wild-type Cyclin F. In this study, we generated the first reported mouse model of endogenous CcnfS621G using CRISPR/Cas9. Neither heterozygous nor homozygous CcnfS621G mice exhibited motor decline or neuronal loss within 18 months. However, through this period mice presented behavioural alterations congruent with early FTD phenotypes. Immunohistochemistry identified alterations in hippocampal astrocyte morphology, including increased ramification, and proteomic analyses identified significant alterations in pathways linked to translation, mitochondrial function, cytoskeletal remodeling and neuroinflammatory signaling. Consistent with this, increased astrocyte ramification was also identified in human sporadic ALS and ALS-FTD post mortem tissue, as well as in human CCNFS621G induced pluripotent stem cell (iPSC)-derived astrocytes. A common phenotype observed in familial and sporadic ALS is alterations in neuronal excitability and loss of repetitive action potential firing. ALS patients and cell and animal models display an early increase in neuronal excitability (hyperexcitability), followed by a decrease in excitability (hypoexcitability) as neurodegeneration progresses. Thus, we reasoned that alterations in CCNFS621G iPSC-derived astrocytes may impact neuronal excitability in co-cultures. CCNFS621G iPSC-derived motor neurons cultured without astrocytes exhibited increased action potential firing, compared to isogenic control neurons, consistent with neuronal hyperexcitability. However, the addition of CCNFS621G astrocytes, but not isogenic control astrocytes, abolished repetitive action potential firing in both CCNFS621G and isogenic control neurons. CCNFS621G astrocytes also increased the population of neurons that failed to fire action potentials and reduced voltage-gated sodium currents in either CCNFS621G or isogenic control neurons. Together, these results suggest that astrocyte activation is an early feature of neurodegenerative disease, occurring in the absence of neuronal loss in CcnfS621G mice and is present with region-specific severity in sporadic ALS and ALS-FTD post mortem tissue. Furthermore, astrocyte-mediated loss of repetitive firing could play a critical role in pre-symptomatic disease stages of CCNF-mediated ALS and FTD pathology.
HostingRepository	PRIDE
AnnounceDate	2026-05-07
AnnouncementXML	Submission_2026-05-06_22:56:47.362.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD064648
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Albert Lee
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-04 19:01:59	ID requested
⏵ 1	2026-05-06 22:56:48	announced

10.6019/PXD064648;

10.1186/S12974-026-03827-X;

submitter keyword: proteomics, brain,ALS, mouse, CCNF, MND, neurodegeneration, cyclin F

Albert Lee
contact affiliation	Motor Neuron Disease Research Centre, Macquarie University, NSW, 2113, Australia
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. PXD064648
     1. Label: PRIDE project
     2. Name: ALS-FTD-linked CCNFS621G Drives Increased Astrocyte Ramification, Alterations in the Proteome Related to Translation, Mitochondrial Function and Neuroinflammation, and Reduced Motor Neuron Excitability