The PLP mutants from mouse to man

Duncan, Ian D.

doi:10.1016/j.jns.2004.10.011

Cited by 20 publications

(12 citation statements)

References 13 publications

(14 reference statements)

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“…The lethal phenotypes of natural PLP1-mutations in mouse and man are best explained by toxic gain-of-function (Duncan, 2005;Garbern, 2007;Miller et al, 2003), but the genuine function of PLP has remained elusive for a long time. Upon the analysis of PLP null -mice, PLP emerged as a ''molecular strut''' to stabilize compact myelin at the intraperiod lines (Mobius et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…While PLP expression is strongly enriched in oligodendrocytes, M6B is found in both oligodendrocytes and neurons (Yan et al, 1993) and at low level in many tissues (Werner et al, 2001). Mutations affecting the human PLP1 gene cause Pelizaeus-Merzbacher disease (Duncan, 2005;Garbern, 2007). Conversely, no disease has been linked to GPM6B, while altered M6B-expression was reported for autism (Purcell et al, 2001), amyotrophic lateral sclerosis (Dangond et al, 2004), glioblastoma (Castells et al, 2010), and suicide-completors (Fiori et al, 2011), although no causative involvement in the pathophysiology of oligodendrocytes or other cells has been reported.…”

Section: Overlapping But Nonidentical Functions Of Myelin Proteolipidsmentioning

confidence: 99%

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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

103

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Overlapping But Nonidentical Functions Of Myelin Proteolipidsmentioning

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

103

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“…Numerous genetic mutations have been reported to interfere with myelination, either by affecting myelin lipid synthesis or breakdown, or by detrimentally affecting myelin-specific proteins (Duncan, 2005). Proper myelination of neuronal axons requires precise coordination of protein and lipid synthesis, their integration into oligodendrocyte membranes, as well as their subsequent breakdown and recycling.…”

Section: Other Genetic Disruptions In Myelinogenesismentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,218

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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“…Notably, some missense mutations found in patients are also naturally occurring in mice. For example, the A242V amino acid substitution, that causes a severe form of PMD in humans, is found in the myelin synthesis-deficient ( msd ) mouse, whereas the I186T mutation, which results in a milder disease in humans, is found in the rumpshacker ( rsh ) mouse (Duncan, 2005). Another mutant, the jimpy ( jp ) mouse, has been extensively used as a PMD model, even if the same mutation is not found in humans (Baumann and Pham-Dinh, 2001).…”

Section: Er Protein Quality Control and Myelin Diseases Of The Cnsmentioning

confidence: 99%

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

Volpi¹,

Touvier²,

D’Antonio³

2017

Front. Mol. Neurosci.

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Reaching the correct three-dimensional structure is crucial for the proper function of a protein. The endoplasmic reticulum (ER) is the organelle where secreted and transmembrane proteins are synthesized and folded. To guarantee high fidelity of protein synthesis and maturation in the ER, cells have evolved ER-protein quality control (ERQC) systems, which assist protein folding and promptly degrade aberrant gene products. Only correctly folded proteins that pass ERQC checkpoints are allowed to exit the ER and reach their final destination. Misfolded glycoproteins are detected and targeted for degradation by the proteasome in a process known as endoplasmic reticulum-associated degradation (ERAD). The excess of unstructured proteins in the ER triggers an adaptive signal transduction pathway, called unfolded protein response (UPR), which in turn potentiates ERQC activities in order to reduce the levels of aberrant molecules. When the situation cannot be restored, the UPR drives cells to apoptosis. Myelin-forming cells of the central and peripheral nervous system (oligodendrocytes and Schwann cells) synthesize a large amount of myelin proteins and lipids and therefore are particularly susceptible to ERQC failure. Indeed, deficits in ERQC and activation of ER stress/UPR have been implicated in several myelin disorders, such as Pelizaeus-Merzbacher and Krabbe leucodystrophies, vanishing white matter disease and Charcot-Marie-Tooth neuropathies. Here we discuss recent evidence underlying the importance of proper ERQC functions in genetic disorders of myelinating glia.

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The PLP mutants from mouse to man

Cited by 20 publications

References 13 publications

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

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

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

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