Gasdermin D palmitoylation: to cleave or not to cleave?

Recent studies have identified Cys191 in gasdermin D (GSDMD) as a highly targeted regulatory module controlling pyroptosis. Using chemical biology and genetic models, Du, Healy et al. recently identified GSDMD palmitoylation as a key regulatory step in GSDMD activation.

A novel high-throughput screening strategy for targeting alpha-synuclein and other long-lived proteins.

Small-molecule high-throughput screening (HTS) campaigns have frequently been used to identify lead molecules that can alter expression of disease-relevant proteins in cell-based assays. However, most cell-based HTS assays require short compound exposure periods to avoid toxicity and ensure that compounds are stable in media for the duration of the exposure. This limits the ability of HTS assays to detect inhibitors of the synthesis of target proteins with long half-lives, which can often exceed the exposure times utilized in most HTS campaigns. One such target is alpha-synuclein (α-syn)-a protein well-known for its pathological aggregation in Parkinson's Disease (PD) and other forms of neurodegeneration known collectively as synucleinopathies. Here, we report the development of an HTS assay using a CRISPR-engineered neuroblastoma cell line expressing a destabilized luciferase reporter inserted at the end of the coding region of the SNCA locus. The resultant destabilized fusion protein exhibited a significant reduction in half-life compared to the endogenous, unmodified α-syn protein, and accurately reported reductions in α-syn levels due to known protein translation inhibitors and specific α-syn siRNAs. The robustness and utility of this approach was shown by using the resulting cell line (dsLuc-Syn) to screen a focused library of 3,192 compounds for reduction of α-syn. These data demonstrate the general utility of converting endogenous loci into destabilized reporter genes capable of identifying inhibitors of gene expression of highly stable proteins even in short-term assays.

Psychology at the table: Voices of elected officials and advocates.

Psychologists have generally not considered advocacy a significant part of their professional activities. At the same time, federal and state public policies create laws and regulations that significantly impact the profession and the public. This article encourages psychologists to become involved in public policy and describes various methods for becoming engaged. Examples of psychologists who have devoted significant aspects of their professional careers to participation in public policy making are given. Congressman Alan Lowenthal's journey from psychologist to U.S. Congressman is described. Also included are reflections and recommendations from a psychologist who serves as an elected school board member, a state psychological association advocacy leader, and the American Psychological Association's Congressional Government affairs director. Public sector psychologists are especially encouraged to engage in political advocacy and to use their experiences to inform policymakers about psychology research and practice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Period protein homolog LIN-42 regulates germline development in C. elegans.

Germline stem cells are maintained in the distal region of the C. elegans gonad. These cells undergo mitotic divisions, and GLP-1/Notch signaling dictates whether they remain in this state. The somatic distal tip cell (DTC) caps the end of the distal gonad and is essential for maintenance of the germline mitotic zone. As germ cells move away from the DTC they exit mitosis and enter early meiotic prophase. Here we identify the Period protein homolog LIN-42 as a new regulator of germline development in C. elegans. LIN-42 is expressed in almost all somatic cells including the DTC, and LIN-42 functions as a transcription factor in the heterochronic pathway and to regulate molting. We found that the mitotic proliferative zone size in the distal gonad was significantly reduced by ~25% in lin-42 mutants compared to WT N2 worms. A lin-42 mutation also reduced the mitotic proliferative zone size caused by glp-1 partial loss-of-function and gain-of-function alleles. LIN-42 mediates this effect, at least in part, by regulating expression of the GLP-1/Notch ligand LAG-2. We further show that lin-42 expression itself is regulated by ATX-2, which promotes germline proliferation and is the homolog of the RNA binding protein ataxin-2 that is implicated in human neurodegenerative diseases. Altogether our results establish a new role for the conserved, important Period protein homolog LIN-42 in regulating early germline development. These results also suggest that in addition to regulating behavioral rhythms, the circadian clock plays an important role in communicating environmental signals to essential reproductive pathways.