Cofilin 1 promotes the pathogenicity and transmission of pathological α-synuclein in mouse models of Parkinson’s disease

The pathological hallmark of Parkinson’s disease (PD) is the presence of Lewy bodies (LBs) with aggregated α-synuclein being the major component. The abnormal α-synuclein aggregates transfer between cells, recruit endogenous α-synuclein into toxic LBs, and finally trigger neuronal injury. However, the molecular mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Previously we found that cofilin 1, a member of the actin-binding protein, promotes the aggregation and pathogenicity of α-synuclein in vitro. Here we further investigated the effect of cofilin 1 in mouse models of PD. We found that the mixed fibrils composed of cofilin 1 and α-synuclein are more pathogenic to mice and more prone to propagation than pure α-synuclein fibrils. Overexpression of cofilin 1 enhances the seeding and spreading of α-synuclein aggregates, and induces PD-like behavioral impairments in mice. Together, these results illustrate the important role of cofilin 1 in the pathogenicity and transmission of α-synuclein during the onset and progression of PD.

Properties and proximity proteomics of synaptopodin provide insight into the molecular organization of the spine apparatus of dendritic spines

The spine apparatus is a specialization of the neuronal ER in dendritic spines consisting of stacks of interconnected cisterns separated by a dense matrix. Synaptopodin, a specific actin binding protein of the spine apparatus, is essential for its formation, but the underlying mechanisms remain unknown. We show that synaptopodin, when expressed in fibroblasts, forms actin-rich structures with connections to the ER, and that an ER-tethered synaptopodin assembles into liquid condensates. We also identified protein neighbors of synaptopodin in spines by in vivo proximity biotinylation. We validated a small subset of such proteins and showed that they co-assemble with synaptopodin in living cells. One of them is Pdlim7, an actin binding protein not previously identified in spines, and we show its precise colocalization with synaptopodin. We suggest that the matrix of the spine apparatus has the property of a liquid protein condensate generated by a multiplicity of low affinity interactions.

Differential expression of coactosin like F-actin binding protein 1 in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding coactosin like F-actin binding protein 1, COTL1, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. COTL1 expression was significantly higher in high-grade serous ovarian tumors relative to normal fallopian tube. COTL1 expression correlated with overall survival in patients with ovarian cancer. These data indicate that expression of COTL1 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. COTL1 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

VASP mediated actin dynamics activate and recruit a filopodia myosin

Filopodia are thin, actin-based structures that cells use to interact with their environments. Filopodia initiation requires a suite of conserved proteins but the mechanism remains poorly understood. The actin polymerase VASP and a MyTH-FERM (MF) myosin, DdMyo7 in amoeba, are essential for filopodia initiation. DdMyo7 is localized to dynamic regions of the actin-rich cortex. Analysis of VASP mutants and treatment of cells with anti-actin drugs shows that myosin recruitment and activation in Dictyostelium requires localized VASP-dependent actin polymerization. Targeting of DdMyo7 to the cortex alone is not sufficient for filopodia initiation; VASP activity is also required. The actin regulator locally produces a cortical actin network that activates myosin and together they shape the actin network to promote extension of parallel bundles of actin during filopodia formation. This work reveals how filopodia initiation requires close collaboration between an actin binding protein, the state of the actin cytoskeleton and MF myosin activity.

A Pan-Cancer Analysis of the Oncogenic Role of Twinfilin Actin Binding Protein 1 in Human Tumors

BackgroundUnderstanding common and unique mechanisms driving oncogenic processes in human tumors is indispensable to develop efficient therapies. Recent studies have proposed Twinfilin Actin Binding Protein 1 (TWF1) as a putative driver gene in lung cancer, pancreatic cancer and breast cancer, however a systematic pan-cancer analysis has not been carried out.MethodsHere, we set out to explore the role of TWF1 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), and several bioinformatic tools.ResultsAs part of our analysis, we have assessed TWF1 expression across tumors. We found that over-expression of TWF1 generally predicted poor OS for patients with tumors with high TWF1 expression, such as mesothelioma, lung adenocarcinoma, cervical cancer and pancreatic adenocarcinoma. We also assessed the mutation burden of TWF1 in cancer and the TWF1-associated survival of cancer patients, compared the phosphorylation of TWF1 between normal and primary tumor tissues and explored putative functional mechanisms in TWF1-mediated oncogenesis.ConclusionsOur pan-cancer analysis provides a comprehensive overview of the oncogenic roles of TWF1 in multiple human cancers.

Dbnl and β-catenin promote pro-N-cadherin processing to maintain apico-basal polarity

The neural tube forms when neural stem cells arrange into a pseudostratified, single-cell–layered epithelium, with a marked apico-basal polarity, and in which adherens junctions (AJs) concentrate in the subapical domain. We previously reported that sustained β-catenin expression promotes the formation of enlarged apical complexes (ACs), enhancing apico-basal polarity, although the mechanism through which this occurs remained unclear. Here, we show that β-catenin interacts with phosphorylated pro-N-cadherin early in its transit through the Golgi apparatus, promoting propeptide excision and the final maturation of N-cadherin. We describe a new β-catenin–dependent interaction of N-cadherin with Drebrin-like (Dbnl), an actin-binding protein that is involved in anterograde Golgi trafficking of proteins. Notably, Dbnl knockdown led to pro-N-cadherin accumulation and limited AJ formation. In brief, we demonstrate that Dbnl and Drebrin-like β-catenin assist in the maturation of pro-N-cadherin, which is critical for AJ formation and for the recruitment AC components like aPKC and, consequently, for the maintenance of apico-basal polarity.