Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway.
The standard score in the 'mental processing composite' scale of the Kaufman-ABC was identical in the spinal muscular atrophy group and controls (103.8).
We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.
Our study presents evidence linking disruption of actin cytoskeletal dynamics to SMA pathogenesis and, for the first time, identifies RhoA effectors as viable targets for therapeutic intervention in the disease.
The transformation to a myofibroblast-like cell phenotype was identified in both LC cells exposed to stiffer substrates, as indicated by an increased α-SMA signal and its colocalization with the actin stress fibers.
To test this, we examined the ability of other known actin cytoskeleton organizing proteins to modify motor axon outgrowth phenotypes in an smn morphant zebrafish model of SMA.
Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling.
Immunohistochemistry to detect integrin α11 and α-SMA was performed on FF and FFPE samples. qPCR for integrin α11 (ITGA11) and α-SMA (ACTA2) was performed on FF samples.
Moreover, we revealed that plasma norepinephrine levels are elevated in SMA mice, which contributes to mechanical hypersensitivity via the β2-adrenergic receptor.
Private ART laboratory.Two couples undergoing IVF for infertility therapy, both of whom had previously delivered offspring afflicted with spinal muscular atrophy (type 1) after IVF therapy, and who underwent subsequent cycles of IVF coupled with PGD to screen for this disorder.
In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA.
In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA.
We reported recently that NMDA receptor activation, directly in the spinal cord, significantly enhanced the transcription rate of the SMN2 genes in a mouse model of very severe SMA (referred as type 1) by a mechanism that involved AKT/CREB pathway activation.
This study advances our understanding of the exercise biology of SMA and highlights the AMPK-p38-PGC-1α axis as a potential regulator of SMN expression alongside AKT and ERK/ELK1 signalling.
Expression of SMN solely in skeletal muscle using the human skeletal actin (HSA) promoter resulted in no improvement of the SMA phenotype or extension of survival.
Mutations in many of these RBPs are associated with neurological diseases, including FMRP in fragile X syndrome; TDP-43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of motor neuron protein) in spinal muscular atrophy.
Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice.