Motor Neuron Dysfunction Research Articles

Homeostatic plasticity can be induced and expressed to restore synaptic strength at neuromuscular junctions undergoing ALS-related degeneration.

Amyotrophic lateral sclerosis (ALS) is debilitating neurodegenerative disease characterized by motor neuron dysfunction and progressive weakening of the neuromuscular junction (NMJ). Hereditary ALS is strongly associated with variants in the human C9orf72 gene. We have characterized C9orf72 pathology at the Drosophila NMJ and utilized several approaches to restore synaptic strength in this model. First, we demonstrate a dramatic reduction in synaptic arborization and active zone number at NMJs following C9orf72 transgenic expression in motor neurons. Further, neurotransmission is similarly reduced at these synapses, consistent with severe degradation. However, despite these defects, C9orf72 synapses still retain the ability to express presynaptic homeostatic plasticity, a fundamental and adaptive form of NMJ plasticity in which perturbation to postsynaptic neurotransmitter receptors leads to a retrograde enhancement in presynaptic release. Next, we show that these endogenous but dormant homeostatic mechanisms can be harnessed to restore synaptic strength despite C9orf72 pathogenesis. Finally, activation of regenerative signaling is not neuroprotective in motor neurons undergoing C9orf72 toxicity. Together, these experiments define synaptic dysfunction at NMJs experiencing ALS-related degradation and demonstrate the potential to activate latent plasticity as a novel therapeutic strategy to restore synaptic strength.

Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS.

Proteostasis disturbance in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motoneurons in the brain and spinal cord leading to paralysis and death. Although the etiology of ALS remains poorly understood, abnormal protein aggregation and altered proteostasis are common features of sporadic and familial ALS forms. The proteostasis network is decomposed into different modules highly conserved across species and comprehends a collection of mechanisms related to protein synthesis, folding, trafficking, secretion and degradation that is distributed in different compartments inside the cell. Functional studies in various ALS models are revealing a complex scenario where distinct and even opposite effects in disease progression are observed depending on the targeted component of the proteostasis network. Importantly, alteration of the folding capacity of the endoplasmic reticulum (ER) is becoming a common pathological alteration in ALS, representing one of the earliest defects observed in disease models, contributing to denervation and motoneuron dysfunction. Strategies to target-specific components of the proteostasis network using small molecules and gene therapy are under development, and promise interesting avenues for future interventions to delay or stop ALS progression.

Laughter, crying and sadness in ALS

BackgroundPseudobulbar affect (PBA) is prevalent in amyotrophic lateral sclerosis (ALS), but there is limited information on its associations and course.ObjectivesExplore prevalence, associations, course and manifestations of PBA in outpatient cohort...

Therapeutic approaches for spinal muscular atrophy (SMA).

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1. Following successful studies on disease models and intensive studies on SMN functions in the past decade, SMN upregulation targeting SMN2, has been suggested as a possible therapeutic approach. Recently, we have witnessed an historical turning point with the first disease-modifying treatment receiving Food and Drug Administration approval and now being available to patients also outside the clinical trial. This innovative treatment is an antisense oligonucleotide, which, administered intrathecally, is able to increase exon 7 inclusion in the majority of the SMN2 mRNA and increase the production of fully functional SMN protein. Alternative advanced therapies, such as viral vector mediated gene therapy and orally available small molecules, are also showing promising results in early clinical trial phases.

Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy.

Spinal muscular atrophy (SMA), the predominant form of motoneuron disease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn-deficient motoneurons, which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN upregulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for therapy, which possibly could be supported by additional strategies that strengthen synaptic transmission.

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contribution of their synaptic partners to the disease process is largely unknown. Here, we show that in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission we observed a decrease in the motor neuron firing which could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Increasing neuronal activity pharmacologically by chronic exposure in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

RNA-seq analyses reveal that cervical spinal cords and anterior motor neurons from amyotrophic lateral sclerosis subjects show reduced expression of mitochondrial DNA-encoded respiratory genes, and rhTFAM may correct this respiratory deficiency

Amyotrophic lateral sclerosis (ALS) is a generally fatal neurodegenerative disease of adults that produces weakness and atrophy due to dysfunction and death of upper and lower motor neurons. We used RNA-sequencing (RNA-seq) to analyze expression of all mitochondrial DNA (mtDNA)-encoded respiratory genes in ALS and CTL human cervical spinal cords (hCSC) and isolated motor neurons. We analyzed with RNA-seq mtDNA gene expression in human neural stem cells (hNSC) exposed to recombinant human mitochondrial transcription factor A (rhTFAM), visualized in 3-dimensions clustered gene networks activated by rhTFAM, quantitated their interactions with other genes and determined their gene ontology (GO) families.RNA-seq and quantitative PCR (qPCR) analyses showed reduced mitochondrial gene expression in ALS hCSC and ALS motor neurons isolated by laser capture microdissection (LCM), and revealed that hNSC and CTL human cervical spinal cords were similar. Rats treated with i.v. rhTFAM showed a dose-response increase in brain respiration and an increase in spinal cord mitochondrial gene expression. Treatment of hNSC with rhTFAM increased expression of mtDNA-encoded respiratory genes and produced one major and several minor clusters of gene interactions. Gene ontology (GO) analysis of rhTFAM-stimulated gene clusters revealed enrichment in GO families involved in RNA and mRNA metabolism, suggesting mitochondrial-nuclear signaling.In postmortem ALS hCSC and LCM-isolated motor neurons we found reduced expression of mtDNA respiratory genes. In hNSC’s rhTFAM increased mtDNA gene expression and stimulated mRNA metabolism by unclear mechanisms. rhTFAM may be useful in improving bioenergetic function in ALS.

Potassium channel abnormalities are consistent with early axon degeneration of motor axons in the G127X SOD1 mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, which selectively affects upper and lower motoneurones. The underlying pathophysiology of the disease is complex but electrophysiological studies of peripheral nerves in ALS patients as well as human autopsy studies indicate that a potassium channel dysfunction/loss is present early in the symptomatic phase. It remains unclear to what extent potassium channel abnormalities reflect a specific pathogenic mechanism in ALS. The aim of this study was therefore to investigate the temporal changes in the expression and/or function of potassium channels in motoneurones in the adult G127X SOD1 mouse model of ALS, a model which has a very long presymptomatic phase. Evidence from animal models indicates that the early progressive motoneurone dysfunction and degeneration can be largely compensated by motor unit remodeling, delaying the clinical symptom onset. Experiments were therefore performed both before and after symptom onset.Immunohistochemistry of motor axons in the ventral roots of G127X SOD1 mice, was used to investigate juxta-paranodal Kv1.2 potassium channels along with nodal Nav1.6 and the paranodal scaffolding protein Caspr. This allowed an investigation of changes in the distribution of Kv1.2 relative to the general structure of the nodal-paranodal-juxta-paranodal complex. This revealed that the motor axons in the ventral roots of presymptomatic G127X SOD1 mice, already show a disruption in juxta-paranodal Kv1.2 potassium channels. The axonal Kv1.2 disruption was preceded by abnormalities in the distribution of the paranodal scaffolding protein Caspr with the nodal arrangement of Nav1.6 appearing relatively preserved even in symptomatic mice. These changes were accompanied by axon swelling and a slowing of conduction in the peripheral motor axons in symptomatic mice. In vivo electrophysiological intracellular recordings of individual spinal motoneurones revealed that central potassium channel function was preserved or even enhanced with higher amplitude and longer duration after-hyperpolarisations in the G127X SOD1 mice.Our data suggest that the potassium channel abnormalities observed in presymptomatic G127X, rather than representing a specific pathophysiological mechanism targeting potassium channels, most likely reflect early axonal degenerative changes, consistent with the “dying-back” phenomenon observed in other ALS models.

Optimizing muscle selection for electromyography in amyotrophic lateral sclerosis.

We compared the yield of limb and thoracic paraspinal muscle examination for revealing lower motor neuron (LMN) dysfunction on electromyography (EMG) in amyotrophic lateral sclerosis (ALS). A retrospective review of 354 patients with clinically definite or probable ALS was performed. Seventeen limb muscles and thoracic paraspinal muscles were evaluated for the presence of both active and chronic denervation. Distal limb muscles showed the highest electrodiagnostic sensitivities of LMN dysfunction in ALS regardless of onset region and diagnostic certainty at the time of diagnosis. Electrodiagnostic yield is higher in muscles from the onset limb. Noncontiguous spread of lower motor neuron degeneration is present in ALS. Optimally selected 6 upper and 5 lower extremity muscles yielded >98% of potential positive cervical or lumbosacral segments. An algorithmic approach to needle EMG in ALS based on pretest probability of individual muscles optimizes electrodiagnostic yield, thus possibly minimizing test duration and patient discomfort. Muscle Nerve 56: 36-44, 2017.

Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis.

The developmental morphogen Sonic hedgehog (Shh) may continue to play a sustaining role in adult motor neurons, of potential relevance to motor neuron diseases including amyotrophic lateral sclerosis. The Shh signaling pathway is incompletely understood and interactions with other signaling pathways are possible. We focus here on Notch, and first show that there is an almost linear reduction in light output from a Gli reporter in Shh Light II cells in the presence of increasing concentrations of the Notch inhibitor DAPT (r2=0.982). Second, in the spinal cord of mutant superoxide dismutase mice, but not control mice, a key marker of Notch signaling changes with age. Before the onset of clinical signs, the Notch intracellular domain is expressed predominantly in motor neurons, but by 125 days of age, Notch intracellular domain expression is markedly reduced in motor neurons and increased in neighboring astroglia. Third, there is a parallel reduction in Gli protein expression in mutant superoxide dismutase mouse spinal motor neurons, consistent with the observed reduction in Notch signaling and also a redistribution of Gli away from the nucleus. Thus, there is a reduction in motor neuronal Notch signaling and associated changes in Shh signaling, occurring coincidentally with disease expression, that may contribute toward the dysfunction and death of motor neurons in amyotrophic lateral sclerosis.

Intermuscular coherence in amyotrophic lateral sclerosis: A preliminary assessment.

Simple laboratory tests of upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) are not available. Intermuscular coherence has been shown to distinguish patients with primary lateral sclerosis, a pure upper motor neuron disorder, from normal subjects, suggesting it could be useful for assessing ALS. We aimed to determine whether intermuscular coherence can distinguish ALS patients from normal subjects. We measured biceps brachii and brachioradialis activity using surface electromyography while subjects held the elbow at flexion and the forearm in semipronation. Intermuscular coherence was calculated at between 20 and 40 Hz in 15 ALS patients and 15 normal subjects. On average, intermuscular coherence was 3.8-fold greater in normal subjects than in ALS patients (P < 0.01), and it distinguished ALS patients from normal subjects with a sensitivity of 87% and specificity of 87%. Intermuscular coherence measurement is a rapid, painless method that may detect upper motor neuron dysfunction in ALS. Muscle Nerve 55: 862-868, 2017.

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2+-mediated cell death signals may be a therapeutic strategy for ALS.

Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.

Hereditary spastic paraplegias (HSPs) are characterized by spasticity and weakness of the lower limbs, resulting from length-dependent axonopathy of the corticospinal tracts. In humans, the HSP-related atlastin genes ATL1-ATL3 catalyze homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using Drosophila, we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability. Broad expression in the nervous system is required to rescue the atlastin-null Drosophila mutant (atl2 ) phenotype. Importantly, both spontaneous release and the reserve pool of synaptic vesicles are affected. Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, possibly in lysosomes. Our findings suggest that trafficking defects produced by Atlastin dysfunction in motor neurons result in redistribution of presynaptic components and aberrant mobilization of synaptic vesicles, stressing the importance of ER-shaping proteins and the susceptibility of motor neurons to their mutations or depletion.

An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with aggregation of TAR DNA-binding protein-43 (TDP-43) in neuronal cells and manifests as motor neuron dysfunction & muscle atrophy. The carboxyl-terminal prion-like domain of TDP-43 can aggregate in vitro into toxic β-sheet rich amyloid-like structures. So far, treatment options for ALS are very limited and Riluzole, which targets glutamate receptors, is the only but highly ineffective drug. Therefore, great interest exists in developing molecules for ALS treatment. Here, we have examined certain derivatives of acridine containing same side chains at position 4 & 5, for inhibitory potential against TDP-43 aggregation. Among several acridine derivatives examined, AIM4, which contains polar carboxyl groups in the side arms, significantly reduces TDP-43-YFP aggregation in the powerful yeast model cell and also abolishes in vitro amyloid-like aggregation of carboxyl terminal domain of TDP-43, as observed by AFM imaging. Thus, AIM4 can be a lead molecule potentiating further therapeutic research for ALS.

Motor neuron disease: biomarker development for an expanding cerebral syndrome

Descriptions of motor neuron disease (MND) documented more than a century ago remain instantly recognisable to the physician. The muscle weakness, typically with signs of upper and lower motor neuron dysfunction, is uniquely relentless. Over the last 30 years, a wider cerebral pathology has emerged, despite the lack of overt cognitive impairment in the majority of patients. From the initial linkage of a small number of cases to mutations in SOD1, diverse cellular pathways have been implicated in pathogenesis. An increasingly complex clinical heterogeneity has emerged around a significant variability in survival. Defining a cellular signature of aggregated TDP-43 common to nearly all MND and a large proportion of frontotemporal dementia (FTD), has placed MND alongside more traditional cerebral neurodegeneration. With new genetic causes, most notably a hexanucleotide expansion in C9orf72 associated with both MND and FTD, the development of biomarkers against which to test therapeutic candidates is a priority.

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.

Anti-Sulfoglucuronosyl Paragloboside Antibody: A Potential Serologic Marker of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. Although the etiology of ALS is obscure, genetic studies of familiar ALS suggest a multifactorial etiology for this condition. Similarly, there probably are multiple causes for sporadic ALS. Autoimmune-mediated motor neuron dysfunction is one proposed etiology for sporadic ALS. In the present study, anti-glycolipid antibodies including GM1, GD1b, GD3, and sulfoglucuronosyl paragloboside (SGPG) were investigated in the sera of a large number of patient samples, including 113 ALS patients and 50 healthy controls, by means of enzyme-linked immunosorbent assay with affinity parametric complex criterion evaluation and thin-layer chromatography immunooverlay (immuno-TLC). Anti-SGPG antibodies were found in the sera of 13.3% ALS patients (15 out of 113). The highest titer reached 1:1600. The presence of anti-SGPG antibodies in the serum samples was also confirmed by immuno-TLC. Importantly, a multiple logistic regression analysis showed that the presence of anti-SGPG antibody was positively correlated with age (p < .01) and negatively correlated with ALS Functional Rating Scale score (p < .05). Moreover, the localization of SGPG-immunoreactivity on the motor neurons of rat spinal cord and a mouse motor neuronal cell line, NSC-34 was observed by an immunofluorescence method. These data suggest that SGPG could represent a specific pathogenic antigen in those ALS patients. The presence of anti-SGPG antibodies in the serum of ALS patients should represent a diagnostic biomarker of ALS, and it could reflect the severity of the disease.

Pathophysiological and diagnostic implications of cortical dysfunction in ALS.

Cortical dysfunction - specifically, the development of hyperexcitability - seems to be an early and intrinsic feature of sporadic and familial amyotrophic lateral sclerosis (ALS) phenotypes, preceding the onset of lower motor neuron dysfunction and correlating with ensuing lower motor neuron dysfunction and degeneration. In fact, cortical dysfunction could provide a pathogenic basis for ALS, with corticomotor neuronal hyperexcitability mediating motor neuron degeneration via a trans-synaptic, glutamate-mediated, excitotoxic mechanism. The recent identification of C9orf72 repeat expansion as an important genetic risk factor for both ALS and frontotemporal dementia has underscored the importance of cortical function in ALS pathogenesis, and has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. Changes in cortical function that develop in ALS could prove useful as diagnostic biomarkers, potentially enhancing the diagnosis of ALS at an early stage of the disease process. Pathophysiological and diagnostic biomarkers of cortical function might also provide insights to guide the development of future therapeutic approaches, including stem cell and genetic interventions, thereby providing potential for more-effective management of patients with ALS.

Nerve Transfer Surgery in Tetraplegia

Objective: Spinal cord injury leads to upper motor neuron paralysis below the level of the injury. However, emerging evidence suggests lower motor neuron denervation is evident in these paralyzed muscle groups. We aimed to study patients with chronic cervical spinal cord injuries who underwent nerve transfer surgery for evidence of lower motor neuron dysfunction in the upper limb preoperatively. Methods: Patients with cervical spine injuries who were being considered for nerve transfer surgery were examined using electromyography for evidence of spontaneous activity in the form of fibrillations. The neuromuscular units were divided into clinically functional “donors”—teres minor, brachialis, and supinator—and into clinically low-functional or nonfunctional “recipients”—flexor digitorum profundus (FDP), flexor pollicis longus (FPL), extensor digitorum communis (EDC), extensor pollicis longus (EPL), and triceps. The aim of the nerve transfer surgery was to restore pivotal upper limb functions such as elbow extension, key pinch, grasp, and release. Results: A retrospective review of the preoperative electromyography results for 25 upper limbs from 17 male patients was performed. A significant proportion of the recipient muscles showed evidence of fibrillations: FDP 96%, triceps 92%, and FPL 91%. Incidence of fibrillations for EDC and EPL was significantly lower despite also being in the recipient group. Interestingly, donor muscle groups with volitional control also showed evidence of fibrillations. Although at a much lower rate than most of the recipient groups, the incidence of fibrillations in the donor muscles were as follows: supinator 8%, brachialis 14%, and teres minor 34%. Conclusion: Patients with cervical spinal cord injury show evidence of lower motor neuron injury on electromyography. This finding has implications for the timing of nerve transfer surgery. The authors propose that, to maximize outcomes, prospective recipient muscles demonstrating denervation should be reinnervated using nerve transfers early (6-12 months post injury) before the neuromuscular endplate degeneration that follows denervation occurs. The presence of fibrillation potentials in prospective donor nerves, which are clinically normal on examination, may have implications for the outcome of nerve transfer surgery using these nerves.