Genetic dissection of oligodendroglial and neuronal<i>Plp1</i>function in a novel mouse model of spastic paraplegia type 2

Lüders, Katja A.; Patzig, Julia; Simons, Mikael; Nave, Klaus‐Armin; Werner, Hauke

doi:10.1002/glia.23193

Cited by 41 publications

(45 citation statements)

References 106 publications

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“…Here, we asked if reducing the abundance of PLP in adult mice has functional or neuropathological consequences. To achieve mice in which the Plp gene can be inactivated in mature oligodendrocytes in a temporally controlled manner, we crossbred mice harboring a floxed Plp allele (Lüders et al, ) with transgenic mice expressing tamoxifen‐inducible Cre ERT2 under control of the Plp promoter ( Plp CreERT2 mice [Leone et al, ]), yielding experimental Plp flox/Y * Plp CreERT2 mice and Plp flox/Y controls. Males of both genotypes were injected i.p.…”

Section: Resultsmentioning

confidence: 99%

“…Considering that Plp null/Y mice display axonal degeneration (de Monasterio‐Schrader et al, ; Edgar et al, ; Griffiths et al, ; Lüders et al, ; Patzig, Erwig, et al, ) qualifying them as a model of SPG2 caused by PLP1 gene mutations in humans, we asked if reducing the abundance of PLP in myelin is sufficient to cause a similar axonopathy. Although the frequency of axon/myelin‐units comprising axonal sproutings (Figure f) or advanced or complete axonal degeneration was not elevated in iKO compared with Ctrl mice (Figure g), axonal spheroids emerged as frequent in iKO mice by 10 months pti (Figure h).…”

Section: Resultsmentioning

confidence: 99%

“…To delete the Plp gene in oligodendrocytes in the adult CNS, we used Plp flox mice in which exon 3 of the Plp gene is flanked by loxP‐sites (Lüders et al, ; Wang et al, ). Plp flox mice were interbred with mice expressing tamoxifen inducible Cre recombinase under control of the Plp promoter ( Plp CreERT2 mice) (Leone et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…The major protein of CNS myelin is a lipid‐associated transmembrane‐tetraspan termed proteolipid protein (PLP) (Folch & Lees, ; Krämer‐Albers, Gehrig‐Burger, Thiele, Trotter, & Nave, ; Milner et al, ; Möbius, Patzig, Nave, & Werner, ; Simons, Kramer, Thiele, Stoffel, & Trotter, ; Werner et al, ). Expression of the Plp ‐gene (official gene name Plp1 ) is highly enriched in oligodendrocytes (Lüders, Patzig, Simons, Nave, & Werner, ; Trapp et al, ). Complete deficiency of PLP in Plp null/Y mice impairs the rate of myelination (de Monasterio‐Schrader et al, ; Yool et al, ), the ultrastructure of myelin (Klugmann et al, ; Patzig, Erwig, et al, ), the abundance in myelin of cholesterol, the deacetylase sirtuin‐2 and filament‐forming septins (Patzig, Erwig, et al, ; Werner et al, ; Werner et al, ), axonal integrity (Edgar et al, ; Griffiths et al, ) as well as motor capabilities (Gould et al, ; Griffiths et al, ; Janova et al, ; Petit et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Lüders

Nessler

Kusch

et al. 2019

Glia

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Proteolipid protein (PLP) is the most abundant integral membrane protein in central nervous system (CNS) myelin. Expression of the Plp‐gene in oligodendrocytes is not essential for the biosynthesis of myelin membranes but required to prevent axonal pathology. This raises the question whether the exceptionally high level of PLP in myelin is required later in life, or whether high‐level PLP expression becomes dispensable once myelin has been assembled. Both models require a better understanding of the turnover of PLP in myelin in vivo. Thus, we generated and characterized a novel line of tamoxifen‐inducible Plp‐mutant mice that allowed us to determine the rate of PLP turnover after developmental myelination has been completed, and to assess the possible impact of gradually decreasing amounts of PLP for myelin and axonal integrity. We found that 6 months after targeting the Plp‐gene the abundance of PLP in CNS myelin was about halved, probably reflecting that myelin is slowly turned over in the adult brain. Importantly, this reduction by 50% was sufficient to cause the entire spectrum of neuropathological changes previously associated with the developmental lack of PLP, including myelin outfoldings, lamellae splittings, and axonal spheroids. In comparison to axonopathy and gliosis, the infiltration of cytotoxic T‐cells was temporally delayed, suggesting a corresponding chronology also in the genetic disorders of PLP‐deficiency. High‐level abundance of PLP in myelin throughout adult life emerges as a requirement for the preservation of white matter integrity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Lüders

Nessler

Kusch

et al. 2019

Glia

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“…PMD is thought to result from a cell-intrinsic deficit within the oligodendrocyte lineage 19 - 23 . In the CNS, PLP (protein) is restricted to oligodendrocytes, but Plp1 transcript and transgene expression have been reported in a few neuronal subsets 24 Since CR- impy mice have constitutive germline Plp1 knockdown in all cells, we generated and validated induced pluripotent stem cells (iPSCs) from isogenic wild-type, CR- impy , and jimpy mice (Extended Data Fig.…”

Section: Main Textmentioning

confidence: 99%

Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

Elitt¹,

Barbar²,

He³

et al. 2018

Preprint

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14 15 Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe 16 neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher 17 disease (PMD). The majority of PLP1 variants, including supernumerary copies and various 18 point mutations, lead to early mortality. However, PLP1-null patients and mice display 19 comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression 20 might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 21 mediated germline knockdown of Plp1 in the severe jimpy (Plp1 jp ) point mutation mouse 22 model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor 23 function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a 24 therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal 25 PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 26 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted 27 ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and 28 extended lifespan through an 8-month endpoint. Collectively, these results support the 29 development of PLP1 suppression as a disease-modifying therapy for most PMD patients. 30 More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes 31 in vivo to modulate neurological function and lifespan, opening a new treatment modality for 32 myelin disorders. 33 2 Main text: 34 Pelizaeus-Merzbacher disease (PMD; OMIM 312080) is an X-linked leukodystrophy 35 typified by extensive hypomyelination of the central nervous system (CNS). Symptoms typically 36 present early in childhood with a constellation of nystagmus, spasticity, hypotonia, and cognitive 37 dysfunction, leading to mortality in early adulthood. In severe forms, symptoms present connatally 38 and patients succumb to their disease in early childhood. Despite intense interest in PMD 39 therapeutic development, including several clinical trials, no disease modifying therapies have 40 proven efficacious in patients 1-6 . 41 Mutations in the proteolipid protein 1 (PLP1; OMIM 300401) gene underlie the 42 pathogenesis of PMD, with variability in disease onset and progression dictated by the severity of 43 the particular mutation 7-9 . PLP1 codes for the tetraspan protein PLP as well as its shorter splice 44 isoform DM20, which lacks 35 amino acids in the cytosolic loop region 10 . PLP/DM20 is highly 45 conserved across species, with human, mouse, and rat sharing identical amino acid sequence 11 . 46 Expression of PLP1 is largely restricted to myelinating oligodendrocytes, where it is responsible 47 53 15 . Null patients can live until 40-60 years old 8,16 , do not develop lower body spastic paraparesis 54 until the second or third decade of life, and do not demonstrate cognitive regression until the third 55 or fourth decade of life (see Extended Data Table 1 for detailed clinical present...

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The wmN1 enhancer region in intron 1 is required for expression of human PLP1

Hamdan

Patyal

Kockara

et al. 2018

Glia

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The myelin proteolipid protein gene (PLP1) encodes the most abundant protein present in myelin from the central nervous system (CNS). Its expression must be tightly controlled as evidenced by mutations that alter PLP1 dosage; both overexpression (elevated PLP1 copy number) and lack thereof (PLP1 deletion) result in X-linked genetic disorders in man. However, not much is known about the mechanisms that govern expression of the human gene. To address this, transgenic mice were generated which utilize human PLP1 (hPLP1) sequences (proximal 6.2 kb of 5'-flanking DNA to the first 38 bp of exon 2) to drive expression of a lacZ reporter cassette. LoxP sites were incorporated around a 1.5-kb section of hPLP1 intron 1 since it contains sequence orthologous to the wmN1 region from mouse which, previously, was shown to augment expression of a minimally-promoted transgene coincident with the active myelination period of CNS development. Eight transgenic lines were generated with the parental, 6.2hPLP(+)Z/FL, transgene. All lines expressed the transgene appropriately in brain as evidenced by staining with X-gal in white matter regions and olfactory bulb. Removal of the "wmN1" region from 6.2hPLP(+)Z/FL with a ubiquitously expressed Cre-driver caused a dramatic reduction in transgene activity. These results demonstrate for the first time that the wmN1 enhancer region: (1) is functional in hPLP1; (2) works in collaboration with its native promoter-not just a basal heterologous promoter; (3) is required for high levels of hPLP1 gene activity; (4) has a broader effect, both spatially and temporally, than originally projected with mPlp1.

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Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

Cited by 41 publications

References 106 publications

Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

The wmN1 enhancer region in intron 1 is required for expression of human PLP1

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