Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet

Saher, Gesine; Rudolphi, Fabian; Corthals, Kristina; Ruhwedel, Torben; Schmidt, K.; Löwel, Siegrid; Dibaj, Payam; Barrette, Benoit; Möbius, Wiebke; Nave, Klaus‐Armin

doi:10.1038/nm.2833

Cited by 109 publications

(111 citation statements)

References 36 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…It could be speculated that PLP overexpression and the sequestration of PLP and cholesterol into LE/Lys has a qualitative or quantitative impact on exosome secretion from oligodendrocytes, which could relate to the myelin degeneration and the axonopathy observed in PLP1 -transgenic animals and PMD patients. Intriguingly, a high cholesterol diet applied to transgenic mice carrying extra copies of PLP1 ameliorated intracellular accumulation of PLP and facilitated myelin formation (Saher et al, 2012), suggesting that the stoichiometric relationship between PLP and cholesterol is important for the mobilization of PLP from the late endocytic pools and proper myelin membrane trafficking.…”

Section: Role Of Membrane Traffic In Myelin Diseasementioning

confidence: 99%

Axon-glia interaction and membrane traffic in myelin formation

White

Krämer-Albers

2014

Front. Cell. Neurosci.

View full text Add to dashboard Cite

In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialized glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarization followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasizing the central role of the Src-family kinase Fyn during central nervous system (CNS) myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of proteolipid protein (PLP) transport by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases.

show abstract

Section: Role Of Membrane Traffic In Myelin Diseasementioning

confidence: 99%

Axon-glia interaction and membrane traffic in myelin formation

White

Krämer-Albers

2014

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…(Saher et al 2012) Currently, there is no effective therapy, although very recently neural stem cells were transplanted into the frontal lobe white matter of four male subjects with an early-onset severe form of PMD. Preliminary results showed improved myelination.…”

Section: Spasticity Disorders Masquerading As Cerebral Palsymentioning

confidence: 99%

A Diagnostic Approach for Cerebral Palsy in the Genomic Era

et al. 2014

View full text Add to dashboard Cite

An ongoing challenge in children presenting with motor delay/impairment early in life is to identify neurogenetic disorders with a clinical phenotype which can be misdiagnosed as cerebral palsy (CP). To help distinguish patients in these two groups, conventional magnetic resonance imaging (MRI) of the brain has been of great benefit in “unmasking” many of these genetic etiologies and has provided important clues to differential diagnosis in others. Recent advances in molecular genetics such as chromosomal microarray and next generation sequencing have further revolutionized the understanding of etiology by more precisely classifying these disorders with a molecular cause. In this paper, we present a review of neurogenetic disorders masquerading as cerebral palsy evaluated at one institution. We have included representative case examples children presenting with dyskinetic, spastic and ataxic phenotypes, with the intent to highlight the time honored approach of using clinical tools of history and examination to focus the subsequent etiologic search with advanced neuroimaging modalities and molecular genetic tools. A precise diagnosis of these masqueraders and their differentiation from CP is important in terms of therapy, prognosis, and family counseling. In summary, this review serves as a continued call to remain vigilant for current and other to-be-discovered neurogenetic masqueraders of cerebral palsy, thereby optimizing care for patients and their families.

show abstract

“…The relevance of the molar PLP-to-cholesterol ratio for trafficking into myelin was recently supported in PLP-overexpressing transgenic mice, a model of Pelizaeus-Merzbacher disease (Werner et al, 1998). In these mice, excess PLP accumulates in oligodendroglial late endosomes/lysosomes, and the addition of supplementary cholesterol was therapeutic by facilitating the incorporation of PLP into myelin (Saher et al, 2012).…”

Section: Association and Cotransport Of Myelin Proteins And Lipidsmentioning

confidence: 99%

A critical role for the cholesterol‐associated proteolipids PLP and M6B in myelination of the central nervous system

Werner

Krämer-Albers

Strenzke

et al. 2013

Glia

Self Cite

103

View full text Add to dashboard Cite

The formation of central nervous system myelin by oligodendrocytes requires sterol synthesis and is associated with a significant enrichment of cholesterol in the myelin membrane. However, it is unknown how oligodendrocytes concentrate cholesterol above the level found in nonmyelin membranes. Here, we demonstrate a critical role for proteolipids in cholesterol accumulation. Mice lacking the most abundant myelin protein, proteolipid protein (PLP), are fully myelinated, but PLP-deficient myelin exhibits a reduced cholesterol content. We therefore hypothesized that "high cholesterol" is not essential in the myelin sheath itself but is required for an earlier step of myelin biogenesis that is fully compensated for in the absence of PLP. We also found that a PLP-homolog, glycoprotein M6B, is a myelin component of low abundance. By targeting the Gpm6b-gene and crossbreeding, we found that single-mutant mice lacking either PLP or M6B are fully myelinated, while double mutants remain severely hypomyelinated, with enhanced neurodegeneration and premature death. As both PLP and M6B bind membrane cholesterol and associate with the same cholesterol-rich oligodendroglial membrane microdomains, we suggest a model in which proteolipids facilitate myelination by sequestering cholesterol. While either proteolipid can maintain a threshold level of cholesterol in the secretory pathway that allows myelin biogenesis, lack of both proteolipids results in a severe molecular imbalance of prospective myelin membrane. However, M6B is not efficiently sorted into mature myelin, in which it is 200-fold less abundant than PLP. Thus, only PLP contributes to the high cholesterol content of myelin by association and co-transport.

show abstract

Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet

Cited by 109 publications

References 36 publications

Axon-glia interaction and membrane traffic in myelin formation

Axon-glia interaction and membrane traffic in myelin formation

A Diagnostic Approach for Cerebral Palsy in the Genomic Era

A critical role for the cholesterol‐associated proteolipids PLP and M6B in myelination of the central nervous system

Contact Info

Product

Resources

About