Highlights d Gut-to-brain propagation of pathologic a-synuclein via the vagus nerve causes PD d Dopamine neurons degenerate in the pathologic a-synuclein gut-to-brain model of PD d Gut injection of pathologic a-synuclein causes PD-like motor and non-motor symptoms d PD-like pathology and symptoms require endogenous a-synuclein

Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of α-syn tetramers. Here, we show that accumulation of GSLs due to GBA1 deficiency decreases α-syn tetramers and related multimers and increases α-syn monomers in CRISPR-GBA1 knockout (KO) SH-SY5Y cells. Moreover, α-syn tetramers and related multimers are decreased in N370S Parkinson's disease (PD) induced pluripotent stem cell (iPSC)-derived human dopaminergic (hDA) neurons and murine neurons carrying the heterozygous L444P mutation. Treatment with miglustat to reduce GSL accumulation and overexpression of GBA1 to augment GBA1 activity reverse the destabilization of α-syn tetramers and protect against α-syn preformed fibril-induced toxicity in hDA neurons. Taken together, these studies provide mechanistic insights into how GBA1 regulates the transition from monomeric α-syn to α-syn tetramers and multimers and suggest unique therapeutic opportunities for PD and dementia with Lewy bodies.

Our method detects single-nucleotide mutations of autosomal recessive diseases as early as the first trimester of pregnancy. This is of importance for metabolic disorders in which early diagnosis can affect management of the disease and reduce complications and anxiety related to invasive testing.

Matrix metalloproteinase (MMP)-9 plays a key role in tumor invasion. Inhibitors of MMP-9 were screened from Metasequoia glyptostroboides (Dawn redwood) and one potent inhibitor, isoginkgetin, a biflavonoid, was identified. Noncytotoxic levels of isoginkgetin decreased MMP-9 production profoundly, but up-regulated the level of tissue inhibitor of metalloproteinase (TIMP)-1, an inhibitor of MMP-9, in HT1080 human fibrosarcoma cells. The major mechanism of Ras-dependent MMP-9 production in HT1080 cells was phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor-KB (NF-KB) activation. Expression of dominant-active H-Ras and p85 (a subunit of PI3K) increased MMP-9 activity, whereas dominant-negative forms of these molecules decreased the level of MMP-9. H-Ras did not increase MMP-9 in the presence of a PI3K inhibitor, LY294002, and a NF-KB inhibitor, SN50. Further studies showed that isoginkgetin regulated MMP-9 production via PI3K/Akt/NF-KB pathway, as evidenced by the findings that isoginkgetin inhibited activities of both Akt and NF-KB. PI3K/Akt is a well-known key pathway for cell invasion, and isoginkgetin inhibited HT1080 tumor cell invasion substantially. Isoginkgetin was also quite effective in inhibiting the activities of Akt and MMP-9 in MDA-MB-231 breast carcinomas and B16F10 melanoma. Moreover, isoginkgetin treatment resulted in marked decrease in invasion of these cells. In summary, PI3K/ Akt is a major pathway for MMP-9 expression and isoginkgetin markedly decreased MMP-9 expression and invasion through inhibition of this pathway. This suggests that isoginkgetin could be a potential candidate as a therapeutic agent against tumor invasion. [Mol Cancer Ther 2006;5(11):2666 -75]

Btg2 is a primary p53 transcriptional target gene which may function as a coactivator-corepressor and/or an adaptor molecule that modulates the activities of its interacting proteins. We have generated Btg2-null mice to elucidate the in vivo function of Btg2. Btg2-null mice are viable and fertile but exhibit posterior homeotic transformations of the axial vertebrae in a dose-dependent manner. Consistent with its role in vertebral patterning, Btg2 is expressed in the presomitic mesoderm, tail bud, and somites during somitogenesis. We further provide biochemical evidence that Btg2 interacts with bone morphogenetic protein (BMP)-activated Smads and enhances the transcriptional activity of BMP signaling. In view of the genetic evidence that reduced BMP signaling causes posteriorization of the vertebral pattern, we propose that the observed vertebral phenotype in Btg2-null mice is due to attenuated BMP signaling.

The ancient wisdom found in iron gall ink guides this work to a simple but advanced solution to the molecular engineering of fluidic interfaces. The Fe(II)–tannin coordination complex, a precursor of the iron gall ink, transforms into interface‐active Fe(III)–tannin species, by oxygen molecules, which form a self‐assembled layer at the fluidic interface spontaneously but still controllably. Kinetic studies show that the oxidation rate is directed by the counteranion of Fe(II) precursor salts, and FeCl2 is found to be more effective than FeSO4—an ingredient of iron gall ink—in the interfacial‐film fabrication. The optimized protocol leads to the formation of micrometer‐thick, free‐standing films at the air–water interface by continuously generating Fe(III)–tannic acid complexes in situ. The durable films formed are transferable, self‐healable, pliable, and postfunctionalizable, and are hardened further by transfer to the basic buffer. This O2‐instructed film formation can be applied to other fluidic interfaces that have high O2 level, demonstrated by emulsion stabilization and concurrent capsule formation at the oil–water interface with no aid of surfactants. The system, inspired by the iron gall ink, provides new vistas on interface engineering and related materials science.

Smad7 inhibits responses mediated by transforming growth factor ␤ (TGF-␤) and acts in a negativefeedback loop to regulate the intensity or duration of the TGF-␤ signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-␤ resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-␤-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-␤ signaling.

S. cerevisiae encapsulated with a poly(norepinephrine)/silica double-layered shell showed multiple resistance to enzymatic attack, desiccation, and UV-C irradiation. The biochemical response of the encapsulated yeast may also contribute to the UV-C resistance.