GM1 promotes TrkA-mediated neuroblastoma cell differentiation by occupying a plasma membrane domain different from TrkA

Recently, we highlighted that the ganglioside GM1 promotes neuroblastoma cells differentiation by activating the TrkA receptor through the formation of a TrkA\u2013GM1 oligosaccharide complex at the cell surface. To study the TrkA\u2013GM1 interaction, we synthesized two radioactive GM1 derivatives presenting a photoactivable nitrophenylazide group at the end of lipid moiety, 1 or at position 6 of external galactose, 2; and a radioactive oligosaccharide portion of GM1 carrying the nitrophenylazide group at position 1 of glucose, 3. The three compounds were singly administered to cultured neuroblastoma Neuro2a cells under established conditions that allow cell surface interactions. After UV activation of photoactivable compounds, the proteins were analyzed by PAGE separation. The formation of cross-linked TrkA\u2013GM1 derivatives complexes was identified by both radioimaging and immunoblotting. Results indicated that the administration of compounds 2 and 3, carrying the photoactivable group on the oligosaccharide, led to the formation of a radioactive TrkA complex, while the administration of compound 1 did not. This underlines that the TrkA\u2013GM1 interaction directly involves the GM1 oligosaccharide, but not the ceramide. To better understand how GM1 relates to the TrkA, we isolated plasma membrane lipid rafts. As expected, GM1 was found in the rigid detergent-resistant fractions, while TrkA was found as a detergent soluble fraction component. These results suggest that TrkA and GM1 belong to separate membrane domains: probably TrkA interacts by \u2018flopping\u2019 down its extracellular portion onto the membrane, approaching its interplay site to the oligosaccharide portion of GM1. (Figure presented.)

Parkinson's disease recovery by GM1 oligosaccharide treatment in the B4galnt1+/- mouse model

Given the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/- mice, a model of sporadic Parkinson's disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral \u3b1-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson's phenotype expressed by the B4galnt1+/- mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson's disease

Mental health policy process: a comparative study of Ghana, South Africa, Uganda and Zambia

<p>Abstract</p> <p>Background</p> <p>Mental illnesses are increasingly recognised as a leading cause of disability worldwide, yet many countries lack a mental health policy or have an outdated, inappropriate policy. This paper explores the development of appropriate mental health policies and their effective implementation. It reports comparative findings on the processes for developing and implementing mental health policies in Ghana, South Africa, Uganda and Zambia as part of the Mental Health and Poverty Project.</p> <p>Methods</p> <p>The study countries and respondents were purposively selected to represent different levels of mental health policy and system development to allow comparative analysis of the factors underlying the different forms of mental health policy development and implementation. Data were collected using semi-structured interviews and document analysis. Data analysis was guided by conceptual framework that was developed for this purpose. A framework approach to analysis was used, incorporating themes that emerged from the data and from the conceptual framework.</p> <p>Results</p> <p>Mental health policies in Ghana, South Africa, Uganda and Zambia are weak, in draft form or non-existent. Mental health remained low on the policy agenda due to stigma and a lack of information, as well as low prioritisation by donors, low political priority and grassroots demand. Progress with mental health policy development varied and respondents noted a lack of consultation and insufficient evidence to inform policy development. Furthermore, policies were poorly implemented, due to factors including insufficient dissemination and operationalisation of policies and a lack of resources.</p> <p>Conclusions</p> <p>Mental health policy processes in all four countries were inadequate, leading to either weak or non-existent policies, with an impact on mental health services. Recommendations are provided to strengthen mental health policy processes in these and other African countries.</p