Expression of the axon‐guidance protein receptor Neuropilin 1 is increased in the spinal cord and decreased in muscle of a mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron disorder. It is supposed that ALS is at least in part an axonopathy. Neuropilin 1 is an important receptor of the axon repellent Semaphorin 3A and a co‐receptor of vascular endothelial growth factor. It is probably involved in neuronal and axonal de‐/regeneration and might be of high relevance for ALS pathogenesis and/or disease progression. To elucidate whether the expression of either Neuropilin1 or Semaphorin3A is altered in ALS we investigated these proteins in human brain, spinal cord and muscle tissue of ALS‐patients and controls as well as transgenic SOD1G93A and control mice. Neuropilin1 and Semaphorin3A gene and protein expression were assessed by quantitative real‐time PCR (qRT‐PCR), western blot and immunohistochemistry. Groups were compared using either Student t‐test or Mann–Whitney U test. We observed a consistent increase of Neuropilin1 expression in the spinal cord and decrease of Neuropilin1 and Semaphorin3A in muscle tissue of transgenic SOD1G93A mice at the mRNA and protein level. Previous studies have shown that damage of neurons physiologically causes Neuropilin1 and Semaphorin3A increase in the central nervous system and decrease in the peripheral nervous system. Our results indicate that this also occurs in ALS. Pharmacological modulation of expression and function of axon repellents could be a promising future therapeutic option in ALS.

Mechanical stimulation of Schwann cells promote peripheral nerve regeneration via extracellular vesicle-mediated transfer of microRNA 23b-3p

“…Nrp1 is a receptor for Semaphorin 3A (Sema3A) and also acts as a co-receptor for vascular endothelial growth factor (VEGF) 72 . Sema3A is an important axon repellent that can induce collapse and paralysis of spinal motor neuron growth cones and activation of Nrp1 results in axon retraction and impaired regeneration 73 . Nrp1 together with its co-receptor plexinA triggers axonal retraction by destabilizing microtubules and microfilament networks.…”

The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

“…Indeed, the pivotal role of satellite cells (SC) as secretors of specific factors and attractive-repulsive signals is essential for axonal guidance and restoration of functional innervation during regeneration [ 16 , 207 ]. For instance, the axis HGF/Sema3A and, recently Neuropilin1/Sema3 have been proposed for regenerative motoneuritogenesis, being the skeletal muscle the main source of SEMA3A [ 16 , 306 ]. Strikingly, in a model of peripheral nerve injury that enables NMJ regeneration, increased SC fusion to myofibers was demonstrated in the vicinity of regenerating NMJs [ 283 ].…”

“…Remarkably, alterations in these secreted signals, including the aforementioned Sema3A and its receptor Neuropilin 1 affect NMJ stability in SOD1 G93A mice [ 306 ]. SEMA3A is a neuro-repellent protein that has the potential to regulate neurite sprouting and seems to be implicated in AChR stability through myogenin [ 207 ].…”

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson’s Disease

“…Nevertheless, several genes related to neural development were upregulated as a result of RT, further supporting that neuromuscular communication and likely physical contact may be altered as a result of PD and modulated by exercise. This was a feature of LV4, wherein a number of genes have been linked to in neurite outgrowth, [e.g., SPTBN1 (spectrin beta 1) and DOCK (dedicators of cytokinesis) 6 and 9 (Miyamoto et al, 2007;Kuramoto et al, 2009;Lee et al, 2012)], neural patterning [e.g., MLLT (myeloid/lymphoid or mixed-lineage leukemia; translocated to)4, TSPAN (tetraspanin)18 (Fairchild and Gammill, 2013;Sai et al, 2017)], and axon guidance [e.g., NRP (neuropilin)1, PLXN (plexin)D1, SEMA (semaphorin)5A (Hilario et al, 2009;Pecho-Vrieseling et al, 2009;Korner et al, 2019)]. Larger studies in the future are necessary to determine whether the gene networks we previously identified as correlates of myofiber grouping are impacted during an RT regimen that partially reverses type I grouping or a completely different gene set is involved.…”