Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.
Rowan SalonerAdam M StaffaroniEric DammerErik C B JohnsonEmily PaolilloAmy WiseHilary HeuerLeah ForsbergArgentina Lario LagoJulia WebbJacob VogelAlexander SantilloOskar HanssonJoel KramerBruce MillerJingyao LiJoseph LoureiroRajeev SivasankaranKathleen WorringerNicholas SeyfriedJennifer S YokoyamaWilliam SeeleySalvatore SpinaLea Tenenholz GrinbergLawren VandeVredePeter LjubenkovEce BayramAndrea BozokiDanielle BrushaberCiaran ConsidineGregory S DayBradford C DickersonKimiko Domoto-ReillyKelley FaberDouglas R GalaskoDaniel H GeschwindNupur GhoshalNeill Graff-RadfordChadwick HalesLawrence S HonigGing-Yuek Robin HsiungEdward HueyJohn KornakWalter KremersMaria I LapidSuzee LeeIrene LitvanCorey McMillanMario F MendezToji MiyagawaAlexander PantelyatMaria B PascualHenry PaulsonLeonard PetrucelliPeter PressmanEliana RamosKatya RascovskyErik D RobersonRodolfo SavicaChristopher GrunseichA Campbell SullivanMaria Carmela TartagliaMarijne VandeberghBradley F BoeveHowie RosenJulio RojasAdam BoxerKaitlin CasalettoPublished in: Research square (2024)
The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations ( C9orf72, GRN, MAPT ) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN ) and extracellular matrix (particularly in MAPT ) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.
Keyphrases
- network analysis
- genome wide
- cerebrospinal fluid
- label free
- extracellular matrix
- poor prognosis
- amyotrophic lateral sclerosis
- dna methylation
- mass spectrometry
- binding protein
- antibiotic resistance genes
- cell death
- multiple sclerosis
- working memory
- oxidative stress
- long non coding rna
- endoplasmic reticulum stress
- gene expression
- late onset
- big data
- case report
- artificial intelligence
- wastewater treatment
- brain injury
- small molecule
- protein protein
- magnetic nanoparticles