AR-12

Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of α-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects α-syn aggregation. Overexpressing FAM171A2 promotes α-syn fibril endocytosis and exacerbates the spread and neurotoxicity of α-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the α-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2–α-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of α-syn fibrils and, thus, as a therapeutic target against PD.

Cancers, particularly lung adenocarcinoma (LUAD), represent a major global health concern. However, the role of FAM72D in various cancers, including LUAD, remains poorly understood.

We utilized databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx) and online tools to investigate the correlation between FAM72D expression and its prognostic, diagnostic, and mutational significance, as well as its impact on immune cell infiltration across multiple cancers. Additionally, we developed LUAD cell lines overexpressing FAM72D to confirm its oncogenic role.

FAM72D expression was elevated in cancerous tissues compared to noncancerous tissues, with diagnostic and prognostic implications in many cancers, including LUAD. Moreover, associations were identified between FAM72D expression and diverse immune subtypes, alongside factors such as microsatellite instability, neoantigens, and tumour mutational burden across pan-cancers. Additionally, FAM72D was associated with immune infiltration and various immune checkpoint-related genes in LUAD. In vitro experiments demonstrated that FAM72D promoted cell proliferation, colony formation, and migration, while inhibiting apoptosis in LUAD cells.

Our study establishes associations between FAM72D expression and diagnosis, prognosis, and tumour immunity across multiple cancers, as well as its oncogenic effects in LUAD. FAM72D shows promise as a biomarker and therapeutic target in LUAD.