Gossip as a Burdened Virtue

Gossip is often serious business, not idle chitchat. Gossip allows those oppressed to privately name their oppressors as a warning to others. Of course, gossip can be in error. The speaker may be lying or merely have lacked sufficient evidence. Bias can also make those who hear the gossip more or less likely to believe the gossip. By examining the social functions of gossip and considering the differences in power dynamics in which gossip can occur, we contend that gossip may be not only permissible but virtuous, both as the only reasonable recourse available and as a means of resistance against oppression

GDNF and Parkinson's Disease : Where Next? A Summary from a Recent Workshop

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.Peer reviewe

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94

SHMT2 drives glioma cell survival in the tumor microenvironment but imposes a dependence on glycine clearance

SUMMARY Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumor microenvironment1–3. Here, we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischemic zones of gliomas. In human glioblastoma multiforme (GBM), mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumor regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumor environment, but also renders these cells sensitive to glycine cleavage system inhibition

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Increased PHGDH expression promotes aberrant melanin accumulation

Background: Copy number gain of the D-3-phosphoglycerate dehydrogenase (PHGDH) gene, which encodes the first enzyme in serine biosynthesis, is found in some human cancers including a subset of melanomas. Methods: In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDH tetO allele that allows tissue-specific, doxycycline-inducible PHGDH expression, and we analyzed the phenotype of mice with a ubiquitous increase in PHGDH expression. Results: Tissues and cells derived from PHGDH tetO mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDH tetO mice reveals the presence of melanin granules in early anagen hair follicles, despite the fact that melanin synthesis is closely coupled to the hair follicle cycle and does not normally begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The aberrant presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in early anagen skin. Conclusions: These data suggest increased PHGDH expression impacts normal melanocyte biology, but PHGDH expression alone is not sufficient to cause cancer.Koch Institute for Integrative Cancer Research (Grant (P30-CA14051)National Science Foundation (U.S.). Graduate Research Fellowship Program (DGE-1122374)Damon Runyon Cancer Research Foundation (Grant DRG-2241-15)Ludwig Center for Molecular Oncology at MIT (Grant 21-CA198028)Ludwig Center for Molecular Oncology at MIT (Grant R01-CA168653

A strategy for the generation, characterization and distribution of animal models by The Michael J. Fox Foundation for Parkinson’s Research

Progress in Parkinson’s disease (PD) research and therapeutic development is hindered by many challenges, including a need for robust preclinical animal models. Limited availability of these tools is due to technical hurdles, patent issues, licensing restrictions and the high costs associated with generating and distributing these animal models. Furthermore, the lack of standardization of phenotypic characterization and use of varying methodologies has made it difficult to compare outcome measures across laboratories. In response, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is directly sponsoring the generation, characterization and distribution of preclinical rodent models, enabling increased access to these crucial tools in order to accelerate PD research. To date, MJFF has initiated and funded the generation of 30 different models, which include transgenic or knockout models of PD-relevant genes such as Park1 (also known as Park4 and SNCA), Park8 (LRRK2), Park7 (DJ-1), Park6 (PINK1), Park2 (Parkin), VPS35, EiF4G1 and GBA. The phenotypic characterization of these animals is performed in a uniform and streamlined manner at independent contract research organizations. Finally, MJFF created a central repository at The Jackson Laboratory (JAX) that houses both non-MJFF and MJFF-generated preclinical animal models. Funding from MJFF, which subsidizes the costs involved in transfer, rederivation and colony expansion, has directly resulted in over 2500 rodents being distributed to the PD community for research use