Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases

Familial dysautonomia （FD） is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein （IKAP） protein production. The disease affects mostly the dorsal root ganglion （DRG） and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhib- itor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings.

Activation mechanisms of clinically distinct B-Raf V600Eand V600K mutants

Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.

A new precision medicine initiative at the dawn of exascale computing

Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.

Pleiotropic tumor suppressor functions of WWOX antagonize metastasis

Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Acquirement of these various hallmarks rely on different cellular pathways,including TGF-βand Wnt signaling.Recently,we reported that WW domain-containing oxidoreductase(WWOX)acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs(miRNAs)in triple-negative breast cancer(TNBC).Here,we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles;further,WWOX interacts with various proteins to exert its tumor suppressor function.Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion,invasion and motility.We further demonstrate that WWOX,through regulation of miR-146a levels,regulates SMAD3,which is a member of the TGF-βsignaling pathway.Moreover,proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled.Altogether,these findings underscore a significant role for WWOX in antagonizing metastasis,further highlighting its role and therapeutic potential in suppressing tumor progression.

Parkin Somatic Mutations Link Melanoma and Parkinson's Disease

Epidemiological studies suggest a direct link between melanoma and Parkinson＇s disease（PD）; however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28 K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson＇s disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.