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Background Elevated SNCA gene expression and intracellular accumulation of the encoded α-synuclein (aSyn) protein are associated with the development of Parkinson disease (PD). To date, few enzymes have been examined for their ability to degrade aSyn. Here, we explore the effects of CTSD gene expression, which encodes the lysosomal protease cathepsin D (CathD), on aSyn processing. Results Over-expression of human CTSD cDNA in dopaminergic MES23.5 cell cultures induced the marked proteolysis of exogenously expressed aSyn proteins in a dose-dependent manner. Unexpectedly, brain extractions, Western blotting and ELISA quantification revealed evidence for reduced levels of soluble endogenous aSyn in ctsd knock-out mice. However, these CathD-deficient mice also contained elevated levels of insoluble, oligomeric aSyn species, as detected by formic acid extraction. In accordance, immunohistochemical studies of ctsd -mutant brain from mice, sheep and humans revealed selective synucleinopathy-like changes that varied slightly among the three species. These changes included intracellular aSyn accumulation and formation of ubiquitin-positive inclusions. Furthermore, using an established Drosophila model of human synucleinopathy, we observed markedly enhanced retinal toxicity in ctsd -null flies. Conclusion We conclude from these complementary investigations that: one, CathD can effectively degrade excess aSyn in dopaminergic cells; two, ctsd gene mutations result in a lysosomal storage disorder that includes microscopic and biochemical evidence of aSyn misprocessing; and three, CathD deficiency facilitates aSyn toxicity. We therefore postulate that CathD promotes 'synucleinase' activity, and that enhancing its function may lower aSyn concentrations in vivo .

We recently discovered that the expression of PRKN , a young-onset Parkinson disease-linked gene, confers redox homeostasis. To further examine the protective effects of parkin in an oxidative stress model, we first combined the loss of prkn with Sod2 haploinsufficiency in mice. Although adult prkn −/− // Sod2 ± animals did not develop dopamine cell loss in the S. nigra , they had more reactive oxidative species and a higher concentration of carbonylated proteins in the brain; bi-genic mice also showed a trend for more nitrotyrosinated proteins. Because these redox changes were seen in the cytosol rather than mitochondria, we next explored the thiol network in the context of PRKN expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, PRKN- linked human cortex and several cell models. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione reductase activity; it also correlated with altered activities of redox-sensitive enzymes in mitochondria isolated from mouse brain (e.g., aconitase-2; creatine kinase). Intriguingly, human parkin itself showed glutathione-recycling activity in vitro and in cells: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S -glutathionylated by the other (GSSG + P-SH → GSH + P- S -SG), including at cysteines 59, 95 and 377. Moreover, parkin’s S -glutathionylation was reversible by glutaredoxin activity. In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, including by parkin’s participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin’s impact on redox homeostasis in the cytosol can affect enzyme activities elsewhere, such as in mitochondria. We posit that antioxidant functions of parkin may explain many of its previously described, protective effects in vertebrates and invertebrates that are unrelated to E3 ligase activity.

We recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. Nevertheless, this rise in oxidative stress led to changes in mitochondrial enzyme activities and the metabolism of glutathione in cells and mammalian brain. In parkin's absence reduced glutathione concentrations were increased including in human cortex. This compensation was not due to new glutathione synthesis but attributed to elevated oxidized glutathione (GSSG)-reductase activity. Moreover, we discovered that parkin also recycled GSSG to its reduced form. With this reaction, parkin became S-glutathionylated, e.g., at cysteines 59 and human-specific 95. This oxidative modification was reversed by glutaredoxin. Our results demonstrate that cytosolic parkin mediates anti-oxidant reactions including H2O2 reduction and glutathione regeneration. These reducing activities lead to a range of oxidative modifications in parkin itself. In parkin-deficient brain oxidative stress rises despite changes to maintain redox balance. Competing Interest Statement The authors have declared no competing interest.

\"As your lifestyle changes, you have different car needs,\" [Nanci] Leitch says. \"It is easy with a lease to change from the sporty car that you had when you were single to a sports utility vehicle when you need one of those with a family ... Now I'm going through my mid-life crisis and really want a Volkswagen Bug.\" Like Leitch and Remer, many consumers are most interested in driving a brand-new car that meets their immediate needs. They want to get the most car for the money. And they would rather invest the difference between lease payments and usually-higher monthly purchase payments into more profitable arenas -- not cars with rapidly depreciating values. Leasing a car involves paying a monthly rate for the use of a car, usually for two or three years. These payments are usually significantly less than the monthly payments on a loan taken out to buy the car. But at the end of the lease the driver has not accumulated any ownership or equity in the car -- so back to the dealer it goes.

To some activists for the disabled, the memorial ignores an important feature of Roosevelt's life and misses the opportunity to honor a role model. The disagreement has sparked a debate over historical accuracy and what Roosevelt would have wanted. The monument under construction, unlike many Washington memorials, will not be a single sculpture but a sequence of outdoor galleries representing Roosevelt's four terms in office. Water fountains, engravings of some of his famous quotes, sculptures of him and his wife, Eleanor, and scenes depicting the Depression will be included. According to Ray Teichman, supervisory archivist at the Rosevelt Library in Hyde Park, N.Y., Roosevelt made public appearances using cruches, leg braces and canes, but even photos of these are rare. In fact, among the 125,000 photographs of him at the library, there is only one showing him in a wheelchair.

Although the United States, by far the world's most entrepreneurial nation, has an annual $60 billion available in private equity for new start-up businesses, entrepreneurs have a tough time getting to it, a study on U.S. entrepreneurship concludes. The Global Entrepreneurship Monitor 1999 National Assessment, a joint study by Babson College and the Kauffman Center for Entrepreneurial Leadership, is scheduled for release at a meeting of the Congressional Economic Leadership Institute in Washington last week.

Caregivers of children requiring tube feeding show growing interest in real-food containing formula, including home-blenderized tube feeding (HBTF) and commercial real-food containing formulas (CRFCF). This study aimed to understand caregivers’ perceptions of both. Caregivers using real-food containing tube feeding were recruited through the Feeding Tube Awareness Foundation Facebook group. A 13-question online survey asked about use of HBTF and CRFCF, beliefs about their choices, and what resources guided formula use. Forty-one completed the survey, with mean child age of 7 years. Overall, 54% (n = 22) used HBTF formulas, 34% (n = 14) CRFCF, and 12% (n = 5) used both. For 70% (n = 29), presence of whole foods, nutritional completeness, and natural ingredients were most important. Challenges with CRFCF use included lack of variety (n = 10, 53%) and cost (n = 9, 47%). HBTF challenges were difficulty preparing away from home (n = 19, 70%) and need for special blenders (n = 15, 56%). Participants believed CRFCF are convenient (n = 35, 85%) and nutritionally consistent (n = 25, 61%), but do not contain enough real-food ingredients (n = 26, 63%). Facebook or other social media was the most valued resource guiding formula use (n = 25, 61%). Caregivers desire formulas that are nutritionally complete and made of whole foods. CRFCF offers convenience and consistency, yet caregivers prefer more real-food ingredients.

Caregivers of children requiring tube feeding show growing interest in real-food containing formula, including home-blenderized tube feeding (HBTF) and commercial real-food containing formulas (CRFCF). This study aimed to understand caregivers' perceptions of both. Caregivers using real-food containing tube feeding were recruited through the Feeding Tube Awareness Foundation Facebook group. A 13-question online survey asked about use of HBTF and CRFCF, beliefs about their choices, and what resources guided formula use. Forty-one completed the survey, with mean child age of 7 years. Overall, 54% (n = 22) used HBTF formulas, 34% (n = 14) CRFCF, and 12% (n = 5) used both. For 70% (n = 29), presence of whole foods, nutritional completeness, and natural ingredients were most important. Challenges with CRFCF use included lack of variety (n = 10, 53%) and cost (n = 9, 47%). HBTF challenges were difficulty preparing away from home (n = 19, 70%) and need for special blenders (n = 15, 56%). Participants believed CRFCF are convenient (n = 35, 85%) and nutritionally consistent (n = 25, 61%), but do not contain enough real-food ingredients (n = 26, 63%). Facebook or other social media was the most valued resource guiding formula use (n = 25, 61%). Caregivers desire formulas that are nutritionally complete and made of whole foods. CRFCF offers convenience and consistency, yet caregivers prefer more real-food ingredients.

Globally, unowned urban cats are a major concern because they may suffer from poor welfare and cause problems, including public health risks, nuisances, and urban wildlife predation. While management options are often presented as a choice between culling or trap–neuter–return (TNR), for 25 years, the Lonely Miaow (Inc.) charity in Auckland, New Zealand (hereafter LM), has used a third strategy—intensive adoption or trap–assess–resolve (TAR). As of 2019, of 14,611 unowned cats trapped, 64.2% were adopted, 22.2% were euthanized if unsocialised or in grave ill-health, 5.7% were neutered and returned to the site, and 7.9% had other outcomes, such as being transferred to other shelters. Adoption rates increased over this time, exceeding 80.0% in 2018 and 2019. The cost of processing each cat from capture to adoption rose from NZD 58 in 1999 to NZD 234 by 2017. Approximately 80% of colonies (sites where cats were trapped) were around residential areas. Approximately 22% of cats required veterinary treatment after capture; common ailments included respiratory infections, ringworm, dental problems, and trauma. Consistently, 52% of cats were young kittens (<10 weeks old), c. 80% of cats were <1 year old, and only c. 2% were estimated to be >5 years old. TAR avoids euthanasia where possible. Its effectiveness would be enhanced by fewer abandonments of owned cats and kittens, fitting within integrated strategies for the control of unowned cats involving community education. Cat adoptions improve the welfare of cats and, with appropriate husbandry, should alleviate concerns about nuisances, public health, and attacks on wildlife or the cats themselves, essentially benefitting the community and the cats. This case study is relevant to other cities around the world that are seeking to manage unowned cats.