Oligodendrocytes: biology and pathology

Oligodendrocytes are the myelinating cells of the central nervous system (CNS). They are the end product of a cell lineage which has to undergo a complex and precisely timed program of proliferation, migration, differentiation, and myelination to finally produce the insulating sheath of axons. Due to this complex differentiation program, and due to their unique metabolism/physiology, oligodendrocytes count among the most vulnerable cells of the CNS. In this review, we first describe the different steps eventually culminating in the formation of mature oligodendrocytes and myelin sheaths, as they were revealed by studies in rodents. We will then show differences and similarities of human oligodendrocyte development. Finally, we will lay out the different pathways leading to oligodendrocyte and myelin loss in human CNS diseases, and we will reveal the different principles leading to the restoration of myelin sheaths or to a failure to do so

The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane.

Genetic defects in myelin formation and maintenance cause leukodystrophies, a group of white matter diseases whose mechanistic underpinnings are poorly understood(1,2). Hypomyelination and congenital cataract (HCC), one of these disorders, is caused by mutations in FAM126A, a gene of unknown function(3). We show that FAM126A, also known as hyccin, regulates the synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P), a determinant of plasma membrane identity(4-6). HCC patient fibroblasts exhibit reduced PtdIns(4)P levels. FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIII alpha and its adaptors TTC7 and EFR3 (refs 5,7). A FAM126A TTC7 alpha-crystal structure reveals an all-alpha-helical heterodimer with a large protein protein interface and a conserved surface that may mediate binding to PI4KIII alpha. Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIII alpha complex in mouse brain and patient fibroblasts. We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides(8-11). Our results point to a role for FAM126A in supporting myelination, an important process in development and also following acute exacerbations in multiple sclerosis(12-14)

Are the stages of change relevant for the development and implementation of a web-based tailored alcohol intervention? A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Computer-tailored programs are a promising tool to stimulate health behavior change, such as reducing alcohol intake. Yet more research is needed to assess whether groups differing in their motivational level to change may need different types of feedback. Furthermore, it is unknown whether motivational level may also determine reactions to computer-tailored interventions. Our aim is to identify the potential relevance of the application of the stages of change concept in the development and implementation of alcohol interventions.</p> <p>Methods</p> <p>A web-based instrument was used to disseminate a questionnaire and to provide tailored feedback messages among adults in the Netherlands (N = 170; 96 females). Motivational level was assessed by the stage of change construct. The survey furthermore assessed alcohol consumption, attitude, social influence, self-efficacy, and program evaluation (i.e., survey items, tailored advice, layout and functionality of the program). The Least Significant Difference method was used to compare people in different stages of change with regard to psychosocial determinants of drinking behavior and program evaluation.</p> <p>Results</p> <p>Of the respondents, 34.1% (n = 58) reported no intention to change to healthier drinking habits in the foreseeable future (precontemplation), 22.9% (n = 39) intended to improve their drinking behavior in the near future (contemplation/preparation) and 42.9% (n = 73) reported to currently adhere to the Dutch alcohol consumption guidelines (action/maintenance). When comparing the three groups, people in the action or maintenance stage reported the lowest number of pros of drinking alcohol, having most healthy drinking role models and the highest levels of self-efficacy regarding healthy drinking in difficult situations, whereas precontemplators reported to receive the least social support regarding healthy drinking. In general, the intervention was positively evaluated, but it seemed to be most appreciated by contemplators and preparers.</p> <p>Conclusions</p> <p>Stage-matched interventions may be useful to encourage people to reduce their alcohol intake. Different factors seem to be important for people in different motivational stages. Longitudinal studies are needed to determine whether these factors also predict stage transition. The intervention could be optimized by tailoring the feedback messages more precisely to the needs of people in different motivational stages, for example by applying the different processes of change.</p