Untitled

Dupree, Jeffrey L.; Coetzee, Timothy; Suzuki, Kinuko; Popko, Brian

doi:10.1023/a:1006908013972

Cited by 75 publications

(25 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This phenotype was delayed postnatally and coincided with the timing of maximum myelination, which prompted the investigation of myelin in these mice. Significant abnormalities, including hypomyelinated and even naked axons, were noted in myelin, although they were less marked than those caused by other gene knockouts, e.g., md rats, quaking mice, and Mag-null and Cgt-null mice 22, 23, 24. Not only were these abnormalities seen in all examined white-matter tracts, but they also were extended to the cranial nerves, including the optic nerve.…”

Section: Main Textmentioning

confidence: 87%

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Chelban

Patel

Vandrovcová

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

show abstract

Section: Main Textmentioning

confidence: 87%

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Chelban

Patel

Vandrovcová

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…In both the NCP1 and CGT mutant mice, paranodal transverse septa were absent ( Fig. 3 B and C; arrowheads) (5,31). At the swellings, the NCP1 and CGT mutant axons displayed severely disorganized and misoriented microtubules (arrows) and neurofilaments (arrowheads) (Fig.…”

Section: Axonal Swellings Display Organelle Accumulation and Cytoskelmentioning

confidence: 94%

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

Garcia-Fresco

Sousa

Pillai

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

View full text Add to dashboard Cite

Axo-glial junctions (AGJs) play a critical role in the organization and maintenance of molecular domains in myelinated axons. Neurexin IV͞Caspr1͞paranodin (NCP1) is an important player in the formation of AGJs because it recruits a paranodal complex implicated in the tethering of glial proteins to the axonal membrane and cytoskeleton. Mice deficient in either the axonal protein NCP1 or the glial ceramide galactosyltransferase (CGT) display disruptions in AGJs and severe ataxia. In this article, we correlate these two phenotypes and show that both NCP1 and CGT mutants develop large swellings accompanied by cytoskeletal disorganization and degeneration in the axons of cerebellar Purkinje neurons. We also show that ␣II spectrin is part of the paranodal complex and that, although not properly targeted, this complex is still formed in CGT mutants. Together, these findings establish a physiologically relevant link between AGJs and axonal cytoskeleton and raise the possibility that some neurodegenerative disorders arise from disruption of the AGJs.myelin ͉ paranodes ͉ cerebellum ͉ ataxia T he anatomical organization of myelinated fibers into distinct domains is the basis for the saltatory mode of action potential propagation. In the axons, these molecular domains (internode, juxtaparanode, paranode, and node of Ranvier) form as a result of specific polarization driven by signaling between the myelinating glial cells and neurons that has yet to be fully understood. In the paranodal region, closely apposed axon-glial membranes form specialized cell junctions, which resemble the ladder-like invertebrate septate junctions, and are referred to as paranodal septate junctions or paranodal axo-glial junctions (AGJs) (1-4).Three major proteins have been shown to localize to the paranodal AGJs: NCP1 (also known as Caspr1 or paranodin) and contactin (CNTN) on the axonal side and neurofascin (NF155), the 155-kDa isoform on the glial side (5-9). Although NF155 is the only known glial protein at the paranodal membrane, a number of nonparanodal glial proteins are required for proper formation, maintenance, and distribution of AGJs, as in the case of ceramide galactosyltransferase (CGT), proteolipid protein, myelin-basic protein, myelin-associated glycoprotein, 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase, and the transcription factor Nkx6-2 (10-17).Genetic ablation of NCP1 and CNTN in mice results in the loss of AGJs and a failure to segregate Na ϩ and K ϩ channels at the nodes and juxtaparanodes, respectively (5, 6). Similar phenotypes were observed at the paranodes in CGT mutants (18,19). CGT encodes an enzyme that is needed for the biosynthesis of two important myelin lipids, galactocerebroside and sulfatide (10,(18)(19)(20)(21). Using subcellular fractionation of NF155 in detergents, Rasband and coworkers (22) proposed a model in which myelin lipids assemble in stable lipid rafts to stabilize the clustering of NF155 at the glial side of AGJs. This model is consistent with the phenotype of CGT mutants in which defective biosynthes...

show abstract

“…Additionally, a comparative proteomic approach was used to compare the expression of proteins in myelin from wild-type and genetically modified CGT-null mice (32,33). These mice are unable to express two key myelin glycosphingolipids, galactocerebroside and sulfatide.…”

Section: Identification and Mapping Of Myelin Proteinsmentioning

confidence: 99%

Proteomic mapping provides powerful insights into functional myelin biology

Taylor

Marta

Claycomb

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

107

View full text Add to dashboard Cite

Myelin is a dynamic, functionally active membrane necessary for rapid action potential conduction, axon survival, and cytoarchitecture. The number of debilitating neurological disorders that occur when myelin is disrupted emphasizes its importance. Using highresolution 2D gel electrophoresis, mass spectrometry, and immunoblotting, we have developed an extensive proteomic map of proteins present in myelin, identifying 98 proteins corresponding to at least 130 of the Ϸ200 spots on the map. This proteomic map has been applied to analyses of the localization and function of selected proteins, providing a powerful tool to investigate the diverse functions of myelin.M yelin is a dynamic, functionally active membrane (1), the loss or damage of which results in serious neurological disorders including leukodystrophies, central and peripheral neuropathies, and inflammatory demyelinating diseases such as multiple sclerosis (2-4). Rapid and efficient action potential conduction in the nervous system depends on myelin, which traditionally has been viewed as a passive contributor to conduction by increasing internodal membrane resistance and decreasing membrane capacitance (5). However, recent work has revealed additional active roles for myelin in nervous system development and function. For example, myelin regulates axon diameter and the formation of axon microtubular networks, and it is a key player in ion channel clustering at nodes of Ranvier (6-11). In return, the axon regulates myelin gene expression (12) and oligodendrocyte survival (13). The functional coupling of myelin and axons is further illustrated by the transfer of phospholipids (14) and N-acetylaspartate (15) from the axon to the myelin sheath.A major impediment to understanding the active biological functions of myelin is the relative lack of myelin proteins that have been described and characterized. Thus, we have undertaken an extensive proteomic analysis of central nervous system myelin, developed a 2D PAGE map of myelin proteins, identified 98 of these proteins, and illustrated the power and utility of this approach through specific applications of comparative proteomics. For example, a comparison of CNS and peripheral nervous system (PNS) myelin proteins has revealed a previously undescribed component of Schwann cell microvilli, a proteomic matching of myelin from normal and genetically modified mice lacking key myelin lipids has demonstrated a dramatic reduction of two newly recognized myelin protein kinases, and an application of the map to a neuroimmunological analysis of demyelinating disease has identified a signaling mechanism (16).

show abstract

Untitled

Cited by 75 publications

References 33 publications

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

Proteomic mapping provides powerful insights into functional myelin biology

Contact Info

Product

Resources

About