scholarly journals A Liquid-to-Solid Phase Transition Enhances the Catalytic Activity of SARM1

2020 ◽  
Author(s):  
Heather S. Loring ◽  
Paul R. Thompson
Keyword(s):  
Phase Transition ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Wallerian Degeneration ◽  
Axonal Degeneration ◽  
Solid Phase ◽  
Neurological Diseases ◽  
Promising Therapeutic Target ◽  
Solid Phase Transition

ABSTRACTSterile alpha and toll/interleukin receptor (TIR) motif–containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to various stressors. The consequent depletion of NAD+ triggers axonal degeneration (i.e., Wallerian degeneration), which is a characteristic feature of neurological diseases, including peripheral neuropathies and traumatic brain injury. Notably, SARM1 knockout mice show minimal degeneration in models of peripheral neuropathy and traumatic brain injury, making SARM1 a promising therapeutic target. However, the development of SARM1 inhibitors has been challenging as the purified enzyme is largely inactive. Herein, we report that SARM1 activity is increased ∼2000–fold by a liquid-to-solid phase transition. These findings provide critical insights into SARM1 biochemistry with important implications for the situation in vivo. Moreover, they will facilitate the discovery of novel SARM1–targeted therapeutics.Graphical Abstract

scholarly journals Liquid-to-solid phase transition of oskar RNP granules is essential for their function in the Drosophila germline

2021 ◽  
Author(s):  
Mainak Bose ◽  
Julia Mahamid ◽  
Anne Ephrussi
Keyword(s):  
Phase Transition ◽  
Solid Phase ◽  
Scaffold Proteins ◽  
Intrinsically Disordered ◽  
Fused In Sarcoma ◽  
Specific Proteins ◽  
Solid Phase Transition ◽  
Rnp Granules

SummaryAsymmetric localization of oskar RNP granules to the oocyte posterior is crucial for abdominal patterning and germline formation of the Drosophila embryo. We show that oskar RNP granules in the oocyte are condensates with solid-like physical properties. Using purified oskar RNA and scaffold proteins Bruno and Hrp48, we confirm in vitro that oskar granules undergo a liquid-to-solid phase transition. Whereas the liquid phase allows RNA incorporation, the solid phase precludes incorporation of additional RNA while allowing RNA-dependent partitioning of specific proteins. Genetic modification of scaffold granule proteins, or tethering the intrinsically disordered region of human Fused in Sarcoma to oskar mRNA, allowed modulation of granule material properties in vivo. The resulting liquid-like properties impaired oskar localization and translation with severe consequences on embryonic development. Our study reflects how physiological phase transitions shape RNA-protein condensates to regulate localization and expression of a maternal RNA that instructs germline formation.

scholarly journals A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Heather S Loring ◽  
Victoria L Czech ◽  
Janneke D Icso ◽  
Lauren O'Connor ◽  
Sangram S Parelkar ◽  
...  
Keyword(s):  
Phase Transition ◽  
Axonal Degeneration ◽  
Neurological Diseases ◽  
Targeted Therapeutics ◽  
Murine Models ◽  
C Elegans ◽  
Nad Glycohydrolase ◽  
Response To Stress ◽  
Interleukin Receptor

Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to stress. NAD+ depletion triggers axonal degeneration, which is a characteristic feature of neurological diseases. Notably, loss of SARM1 is protective in murine models of peripheral neuropathy and traumatic brain injury. Herein, we report that citrate induces a phase transition that enhances SARM1 activity by ~2000-fold. This phase transition can be disrupted by mutating a residue involved in multimerization, G601P. This mutation also disrupts puncta formation in cells. We further show that citrate induces axonal degeneration in C. elegans that is dependent on the C. elegans orthologue of SARM1 (TIR-1). Notably, citrate induces the formation of larger puncta indicating that TIR-1/SARM1 multimerization is essential for degeneration in vivo. These findings provide critical insights into SARM1 biology with important implications for the discovery of novel SARM1-targeted therapeutics.

An Activatable NIR‐II Nanoprobe for In Vivo Early Real‐Time Diagnosis of Traumatic Brain Injury

2019 ◽  
Vol 59 (1) ◽  
pp. 247-252 ◽  
Author(s):  
Chunyan Li ◽  
Wanfei Li ◽  
Huanhuan Liu ◽  
Yejun Zhang ◽  
Guangcun Chen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Real Time ◽  
Time Diagnosis

scholarly journals Using the Olfactory System as an In Vivo Model To Study Traumatic Brain Injury and Repair

2014 ◽  
Vol 31 (14) ◽  
pp. 1277-1291 ◽  
Author(s):  
Elizabeth Steuer ◽  
Michele L. Schaefer ◽  
Leonardo Belluscio
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Olfactory System ◽  
In Vivo Model ◽  
Injury And Repair

Solidification of Ionic Liquids: Theory and Techniques

2010 ◽  
Vol 63 (4) ◽  
pp. 544 ◽  
Author(s):  
Anja-Verena Mudring
Keyword(s):  
Phase Transition ◽  
Ionic Liquid ◽  
Ionic Liquids ◽  
Solid Phase ◽  
Soft Materials ◽  
Separation Science ◽  
Vast Number ◽  
Plastic Crystals ◽  
Thermal Fluids ◽  
Solid Phase Transition

Ionic liquids (ILs) have become an important class of solvents and soft materials over the past decades. Despite being salts built by discrete cations and anions, many of them are liquid at room temperature and below. They have been used in a wide variety of applications such as electrochemistry, separation science, chemical synthesis and catalysis, for breaking azeotropes, as thermal fluids, lubricants and additives, for gas storage, for cellulose processing, and photovoltaics. It has been realized that the true advantage of ILs is their modular character. Each specific cation–anion combination is characterized by a unique, characteristic set of chemical and physical properties. Although ILs have been known for roughly a century, they are still a novel class of compounds to exploit due to the vast number of possible ion combinations and one fundamental question remains still inadequately answered: why do certain salts like ILs have such a low melting point and do not crystallize readily? This Review aims to give an insight into the liquid–solid phase transition of ILs from the viewpoint of a solid-state chemist and hopes to contribute to a better understanding of this intriguing class of compounds. It will introduce the fundamental theories of liquid–solid-phase transition and crystallization from melt and solution. Aside form the formation of ideal crystals the development of solid phases with disorder and of lower order like plastic crystals and liquid crystals by ionic liquid compounds are addressed. The formation of ionic liquid glasses is discussed and finally practical techniques, strategies and methods for crystallization of ionic liquids are given.

Sign in / Sign up

Export Citation Format

Share Document