Filamin A (FLNA) (FLNA)

Filamin A (FLNA) is a high-molecular-weight cytoskeletal protein that organizes actin filaments and acts as a versatile signaling scaffold (UniProt P21333). In Alzheimer's disease pathology, FLNA is reported to adopt an altered conformation that facilitates the toxic signaling of amyloid-beta through the alpha-7 nicotinic acetylcholine receptor and TLR4 (Wang et al., 2017). The VAKGL pentapeptide (Valine-Alanine-Lysine-Glycine-Leucine) is a specific sequence within FLNA identified as the binding site for the investigational drug Simufilam (PTI-125). By targeting this VAKGL motif, the drug is intended to restore FLNA to its functional, native conformation, thereby reducing neuroinflammation and tau hyperphosphorylation (Burns et al., 2021). While FLNA is essential for normal brain development and cell motility, its role as a therapeutic target in neurodegeneration remains a subject of significant scientific debate and ongoing clinical investigation (ClinicalTrials.gov NCT05022030).

Other names

Filamin-1Actin-binding protein 280ABP-280Alpha-filaminNon-muscle filaminFLN1

Simufilam (PTI-125) binds to the VAKGL sequence of an altered conformation of Filamin A, restoring its native shape and preventing its association with alpha-7 nicotinic acetylcholine receptors and TLR4, which reduces amyloid-beta-induced neurotoxicity (Wang et al., 2017; Burns et al., 2021).