Macrophage depletion blocks congenital SARM1-dependent neuropathy.

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss.

SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might activate SARM1. Here, we show the nicotinamide analog 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN, which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration, and neuronal death. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to the peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.

17ß-estradiol regulates the RNA-binding protein Nova1, which then regulates the alternative splicing of estrogen receptor ß in the aging female rat brain.

Alternative RNA splicing results in the translation of diverse protein products arising from a common nucleotide sequence. These alternative protein products are often functional and can have widely divergent actions from the canonical protein. Studies in humans and other vertebrate animals have demonstrated that alternative splicing events increase with advanced age, sometimes resulting in pathological consequences. Menopause represents a critical transition for women, where the beneficial effects of estrogens are no longer evident; therefore, factors underlying increased pathological conditions in women are confounded by the dual factors of aging and declining estrogens. Estrogen receptors (ERs) are subject to alternative splicing, the spliced variants increase following menopause, and they fail to efficiently activate estrogen-dependent signaling pathways. However, the factors that regulate the alternative splicing of ERs remain unknown. We demonstrate novel evidence supporting a potential biological feedback loop where 17ß-estradiol regulates the RNA-binding protein Nova1, which, in turn, regulates the alternative splicing of ERß. These data increase our understanding of ER alternative splicing and could have potential implications for women taking hormone replacement therapy after menopause.

Muscle-derived matrix metalloproteinase regulates stem cell proliferation in planarians.

BACKGROUND: Matrix metalloproteinases (MMPs) are a large family of regulatory enzymes that function in extracellular matrix degradation and facilitate a diverse range of cellular processes. Despite the significant focus on the activities of MMPs in human disease, there is a lack of substantial knowledge regarding their normal physiological roles and their role in regulating aspects of stem cell biology. The freshwater planarian Schmidtea mediterranea (S. mediterranea) is an excellent system in which to study robust and nearly unlimited regeneration, guided by a population of mitotically active stem cells, termed neoblasts. RESULTS: We characterized MMPs in the context of planarian stem cells, specifically exploring the role of S. mediterranea MT-MMPB. Using in situ hybridization and available functional genomic tools, we observed that mt-mmpB is expressed in the dorsoventral muscle cells, and its loss results in a reduction in animal size accompanied by a decrease in mitotic cells, suggesting that it plays a unique role in regulating stem cell proliferation. CONCLUSIONS: The novel findings of this study bring to light the unique and critical roles that muscles play in regulating neoblast function, and more broadly, highlight the importance of MMPs in stem cell biology. Developmental Dynamics 245:963-970, 2016. © 2016 Wiley Periodicals, Inc.