Extracellular alpha-synuclein: Sensors, receptors, and responses

Synucleinopathies are a group of progressive neurodegenerative diseases known for the accumulation of insoluble aggregates containing the protein alpha-synuclein (aSyn). Recently, it has been assumed that pathology spreads in the brain during disease progression, implying that, at some point in the process, aSyn may exist outside of cells. In this context, extracellular-aSyn (e-aSyn) might transduce signals to the inside of the cells it interacts with, and/or be internalized by different types of cells through the extracellular matrix. Both negatively charged lipids and membrane receptors have been hypothesized as modulators of the loss of cellular homeostasis and cytotoxicity, and of the internalization of e-aSyn. Internalized e-aSyn causes the disruption of multiple cellular processes such as the autophagy lysosomal pathway (ALP), mitochondrial function, endoplasmic reticulum (ER)-stress, UPR activation, or vesicular transport. These processes happen not only in neurons but also in glial cells, activating inflammatory or anti-inflammatory pathways that can affect both neuronal function and survival, thereby affecting disease progression. In this review, we explore possible effects e-aSyn, all the way from the extracellular matrix to the nucleus. In particular, we highlight the glial-neuronal relationship as this is particularly relevant in the context of the spreading of aSyn pathology in synucleinopathies

Development of a portfolio of learning for postgraduate family medicine training in South Africa: a Delphi study

<p>Abstract</p> <p>Background</p> <p>Within the 52 health districts in South Africa, the family physician is seen as the clinical leader within a multi-professional district health team. Family physicians must be competent to meet 90% of the health needs of the communities in their districts. The eight university departments of Family Medicine have identified five unit standards, broken down into 85 training outcomes, for postgraduate training. The family medicine registrar must prove at the end of training that all the required training outcomes have been attained. District health managers must be assured that the family physician is competent to deliver the expected service. The Colleges of Medicine of South Africa (CMSA) require a portfolio to be submitted as part of the uniform assessment of all registrars applying to write the national fellowship examinations. This study aimed to achieve a consensus on the contents and principles of the first national portfolio for use in family medicine training in South Africa.</p> <p>Methods</p> <p>A workshop held at the WONCA Africa Regional Conference in 2009 explored the purpose and broad contents of the portfolio. The 85 training outcomes, ideas from the WONCA workshop, the literature, and existing portfolios in the various universities were used to develop a questionnaire that was tested for content validity by a panel of 31 experts in family medicine in South Africa, via the Delphi technique in four rounds. Eighty five content items (national learning outcomes) and 27 principles were tested. Consensus was defined as 70% agreement. For those items that the panel thought should be included, they were also asked how to provide evidence for the specific item in the portfolio, and how to assess that evidence.</p> <p>Results</p> <p>Consensus was reached on 61 of the 85 national learning outcomes. The panel recommended that 50 be assessed by the portfolio and 11 should not be. No consensus could be reached on the remaining 24 outcomes and these were also omitted from the portfolio. The panel recommended that various types of evidence be included in the portfolio. The panel supported 26 of the 27 principles, but could not reach consensus on whether the portfolio should reflect on the relationship between the supervisor and registrar.</p> <p>Conclusion</p> <p>A portfolio was developed and distributed to the eight departments of Family Medicine in South Africa, and the CMSA, to be further tested in implementation.</p