Reduced p75 NTR  expression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis

Küst, B.M.; Brouwer, Nieske; Mantingh, I.; Boddeke, H. W. G. M.; Copray, J.C.V.M.

doi:10.1080/14660820301185

Cited by 18 publications

(14 citation statements)

References 23 publications

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“…Alternatively, AS-PNA may act on other neural cell types. Changes in glial cell proliferation and activation were recently reported in SOD1 G93A double transgenic mice genetically deficient in p75 NTR expression (Kust et al 2003). Extended survival was determined in female mice only, explained by reduced astrogliosis in the spinal cord.…”

Section: Discussionmentioning

confidence: 89%

Antisense peptide nucleic acid‐mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice

Turner

Cheah

Macfarlane

et al. 2003

Journal of Neurochemistry

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Re-expression of the death-signalling p75 neurotrophin receptor (p75 NTR ) is associated with injury and neurodegeneration in the adult nervous system. The induction of p75 NTR expression in mature degenerating spinal motor neurons of humans and transgenic mice with amyotrophic lateral sclerosis (ALS) suggests a role of p75 NTR in the progression of motor neuron disease (MND). In this study, we designed, synthesized and evaluated novel antisense peptide nucleic acid (PNA) constructs targeting p75 NTR as a potential gene knockdown therapeutic strategy for ALS. An 11-mer antisense PNA directed at the initiation codon, but not downstream gene sequences, dose-dependently inhibited p75 NTR expression and death-signalling by nerve growth factor (NGF) in Schwann cell cultures. Antisense phosphorothioate oligonucleotide (PS-ODN) sequences used for comparison failed to confer such inhibitory activity. Systemic intraperitoneal administration of this antisense PNA to mutant superoxide dismutase 1 (SOD1 G93A ) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75 NTR expression and subsequent caspase-3 activation in spinal cords were consistent with increased survival in antisense PNA-treated mice. The uptake of fluorescent-labelled antisense PNA in the nervous system of transgenic mice was also confirmed. This study suggests that p75 NTR may be a promising antisense target in the treatment of ALS. Keywords: amyotrophic lateral sclerosis, antisense, motor neuron, p75 neurotrophin receptor, peptide nucleic acid, superoxide dismutase 1.

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Section: Discussionmentioning

confidence: 89%

Antisense peptide nucleic acid‐mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice

Turner

Cheah

Macfarlane

et al. 2003

Journal of Neurochemistry

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“…Our results suggest that there is a set of signaling factors that are altered, rather than a single pathway that is affected. These observations may explain the limited effects observed when crossing mSOD1 mice with knockouts in pathways that are thought to be important to disease pathology at the cellular level, such as p75 (Küst et al, 2003) FasL−/− (Petri et al, 2006) or Bax−/− (Gould et al, 2006) null mice. In contrast, crossing Loa mice with mSOD1 mice showed some rescue effects both in axonal transport defects and in the life span of the mice (Kieran et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

A Switch in Retrograde Signaling from Survival to Stress in Rapid-Onset Neurodegeneration

Perlson¹,

Jeong²,

Ross³

et al. 2009

J. Neurosci.

162

143

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Retrograde axonal transport of cellular signals driven by dynein is vital for neuronal survival. Mouse models with defects in the retrograde transport machinery including the Loa mouse (point mutation in dynein) and the Tgdynamitin mouse (overexpression of dynamitin) exhibit mild neurodegenerative disease. Transport defects have also been observed in more rapidly progressive neurodegeneration, such as that observed in the SOD1G93A transgenic mouse model for familial ALS. Here we test the hypothesis that alterations in retrograde signaling lead to neurodegeneration. In-vivo, in-vitro and live cell imaging motility assays show mis-regulation of transport and inhibition of retrograde signaling in the SOD1G93A model. However, similar inhibition is also seen in the Loa and Tgdynamitin mouse models. Thus, slowing of retrograde signaling leads only to mild degeneration and cannot explain ALS etiology. To further pursue this question, we used a proteomics approach to investigate dynein-associated retrograde signaling. These data indicate a significant decrease in retrograde survival factors including P-Trk and P-Erk1/2, and an increase in retrograde stress factor signaling, including P-JNK, Caspase-8 and p75NTR cleavage fragment in the SOD1G93A model; similar changes are not seen in the Loa mouse. Co-cultures of motor neurons and glia expressing mutant SOD1 (mSOD1) in compartmentalized chambers indicate that inhibition of retrograde stress signaling is sufficient to block activation of cellular stress pathways and to rescue motor neurons from mSOD1-induced toxicity. Hence, a shift from survival-promoting to death-promoting retrograde signaling may be key to the rapid onset of neurodegeneration seen in ALS.

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“…Up-regulation of proNGF, p75NTR and sortilin was also associated with spongiform encephalomyelopathy [52]. Reduced p75NTR delayed disease onset in female transgenic ALS mice [19], though treatment with a p75NTR antagonist showed no improvement on disease progression [53]. Furthermore, while the lactacystin and 6-OHDA rat models of PD were used in this study, previous evidence showed that they might differ in their mechanism to induce neuronal death; lactacystin might inhibit proteasomes and induce modified protein, and 6-OHDA might function through oxidative stress and induce mitochondrial dysfunction [1,5,6].…”

Section: Resultsmentioning

confidence: 99%

“…The proNGF triggers neuronal cell apoptosis by high-affinity binding to p75NTR, while p75NTR mediates neuronal cell death by formation of the p75NTR-sortilin signaling complex [9,12,13]. In fact, proNGF, p75NTR and sortilin exhibited roles in neurodegeneration of aging, onset or progression in various neurodegenerative diseases like Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and acute trauma of the nervous system [14–19]. Currently, however, there is still a lack of studies on the implication of proNGF-p75NTR-sortilin signaling in pathogenesis or progression of PD.…”

Section: Introductionmentioning

confidence: 99%

Presence of proNGF-Sortilin Signaling Complex in Nigral Dopamine Neurons and Its Variation in Relation to Aging, Lactacystin and 6-OHDA Insults

Xia

Chen

Sun

et al. 2013

IJMS

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Growing evidence has shown that proNGF-p75NTR-sortilin signaling might be a crucial factor in neurodegeneration, but it remains unclear if it may function in nigral neurons under aging and disease. The purpose of this study is to examine and quantify proNGF and sortilin expression in the substantia nigra and dynamic changes of aging in lactacystin and 6-hydroxydopamine (6-OHDA) rat models of Parkinson’s disease using immunofluorescence, electronic microscopy, western blot and FLIVO staining methods. The expression of proNGF and sortilin was abundantly and selectively identified in tyrosine hydroxylase (TH)-containing dopamine neurons in the substantia nigra. These proNGF/TH, sortilin/TH-positive neurons were densely distributed in the ventral tier, while they were less distributed in the dorsal tier, where calbindin-D28K-containing neurons were numerously located. A correlated decrease of proNGF, sortilin and TH was also detected during animal aging process. While increase of proNGF, sortilin and cleaved (active) caspase-3 expression was found in the lactacystin model, dynamic proNGF and sortilin changes along with dopamine neuronal loss were demonstrated in the substantia nigra of both the lactacystin and 6-OHDA models. This study has thus revealed the presence of the proNGF-sortilin signaling complex in nigral dopamine neurons and its response to aging, lactacystin and 6-OHDA insults, suggesting that it might contribute to neuronal apoptosis or neurodegeneration during pathogenesis and disease progression of Parkinson’s disease; the underlying mechanism and key signaling pathways involved warrant further investigation.

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Reduced p75 NTR expression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis

Cited by 18 publications

References 23 publications

Antisense peptide nucleic acid‐mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice

Antisense peptide nucleic acid‐mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice

A Switch in Retrograde Signaling from Survival to Stress in Rapid-Onset Neurodegeneration

Presence of proNGF-Sortilin Signaling Complex in Nigral Dopamine Neurons and Its Variation in Relation to Aging, Lactacystin and 6-OHDA Insults

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