Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins

α-synuclein, β-synuclein, and γ-synuclein are abundantly expressed proteins in the vertebrate nervous system. α-synuclein functions in neurotransmitter release by binding to and clustering synaptic vesicles and chaperoning SNARE-complex assembly. Pathologically, aggregates originating from soluble pools of α-synuclein are deposited into Lewy bodies in Parkinson’s disease and related synucleinopathies. The functions of β-synuclein and γ-synuclein in presynaptic terminals remain poorly studied. Using in vitro liposome binding studies, circular dichroism spectroscopy, immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments on isolated synaptic vesicles in combination with subcellular fractionation of brains from synuclein mouse models, we show that β-synuclein and γ-synuclein have a reduced affinity toward synaptic vesicles compared with α-synuclein, and that heteromerization of β-synuclein or γ-synuclein with α-synuclein results in reduced synaptic vesicle binding of α-synuclein in a concentration-dependent manner. Our data suggest that β-synuclein and γ-synuclein are modulators of synaptic vesicle binding of α-synuclein and thereby reduce α-synuclein’s physiological activity at the neuronal synapse

FOXO protects against age‐progressive axonal degeneration

Summary Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age‐progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system‐specific deletion of Foxo transcription factors in mice accelerates aging‐related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle‐aged Foxo knockout mice that are typically only observed in very old wild‐type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve‐specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself

Fabrication of Core–Shell Nanoparticles via Controlled Aggregation of Semiflexible Conjugated Polymer and Hyaluronic Acid

Core-shell conjugated polymer nanoparticles (CPNs) were fabricated by complexing a semi-flexible, primary amine-containing conjugated polymer (CP) with hyaluronic acid (HA). Flexibility introduced in the rigid rod conjugated backbone allows backbone reorganization to increase π-π interaction under ionic complexation, resulting in core-shell nanoparticles with a hydrophobic CP core wrapped with a HA shell. The core-shell nanoparticles exhibited no cellular toxicity and high cancer cell specificity with minimal binding to normal cells

First Report of Bloodstream Infection Caused by Pseudomonas fulva▿ †

Pseudomonas fulva has not yet been isolated from humans as a pathogen. Herein, we report the first case of P. fulva bacteremia in a patient hospitalized due to trauma. The species was identified using biochemical and molecular genetic analyses of the 16S rRNA, gyrB, rpoB, and rpoD genes

Targeted stabilization of Munc18‐1 function via pharmacological chaperones

Abstract Heterozygous de novo mutations in the neuronal protein Munc18‐1 cause syndromic neurological symptoms, including severe epilepsy, intellectual disability, developmental delay, ataxia, and tremor. No disease‐modifying therapy exists to treat these disorders, and while chemical chaperones have been shown to alleviate neuronal dysfunction caused by missense mutations in Munc18‐1, their required high concentrations and potential toxicity necessitate a Munc18‐1‐targeted therapy. Munc18‐1 is essential for neurotransmitter release, and mutations in Munc18‐1 have been shown to cause neuronal dysfunction via aggregation and co‐aggregation of the wild‐type protein, reducing functional Munc18‐1 levels well below hemizygous levels. Here, we identify two pharmacological chaperones via structure‐based drug design, that bind to wild‐type and mutant Munc18‐1, and revert Munc18‐1 aggregation and neuronal dysfunction in vitro and in vivo, providing the first targeted treatment strategy for these severe pediatric encephalopathies

Fabrication of Core–Shell Nanoparticles via Controlled Aggregation of Semiflexible Conjugated Polymer and Hyaluronic Acid

Fabrication of Core–Shell Nanoparticles via Controlled Aggregation of Semiflexible Conjugated Polymer and Hyaluronic Aci