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1.
N Engl J Med ; 390(12): 1092-1104, 2024 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-38507752

RESUMO

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).


Assuntos
Técnicas de Transferência de Genes , Terapia Genética , Neuropatia Axonal Gigante , Criança , Humanos , Proteínas do Citoesqueleto/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Neuropatia Axonal Gigante/genética , Neuropatia Axonal Gigante/terapia , Transgenes , Injeções Espinhais
2.
Nat Rev Neurosci ; 21(4): 183-196, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152523

RESUMO

Wallerian degeneration is a widespread mechanism of programmed axon degeneration. In the three decades since the discovery of the Wallerian degeneration slow (WldS) mouse, research has generated extensive knowledge of the molecular mechanisms underlying Wallerian degeneration, demonstrated its involvement in non-injury disorders and found multiple ways to block it. Recent developments have included: the detection of NMNAT2 mutations that implicate Wallerian degeneration in rare human diseases; the capacity for lifelong rescue of a lethal condition related to Wallerian degeneration in mice; the discovery of 'druggable' enzymes, including SARM1 and MYCBP2 (also known as PHR1), in Wallerian pathways; and the elucidation of protein structures to drive further understanding of the underlying mechanisms and drug development. Additionally, new data have indicated the potential of these advances to alleviate a number of common disorders, including chemotherapy-induced and diabetic peripheral neuropathies, traumatic brain injury, and amyotrophic lateral sclerosis.


Assuntos
Degeneração Walleriana/metabolismo , Animais , Proteínas do Domínio Armadillo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster , Humanos , Camundongos , Camundongos Transgênicos , NAD/metabolismo , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Transdução de Sinais , Pesquisa Translacional Biomédica
3.
J Physiol ; 602(6): 1127-1145, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38441922

RESUMO

Spectrins function together with actin as obligatory subunits of the submembranous cytoskeleton. Spectrins maintain cell shape, resist mechanical forces, and stabilize ion channel and transporter protein complexes through binding to scaffolding proteins. Recently, pathogenic variants of SPTBN4 (ß4 spectrin) were reported to cause both neuropathy and myopathy. Although the role of ß4 spectrin in neurons is mostly understood, its function in skeletal muscle, another excitable tissue subject to large forces, is unknown. Here, using a muscle specific ß4 spectrin conditional knockout mouse, we show that ß4 spectrin does not contribute to muscle function. In addition, we show ß4 spectrin is not present in muscle, indicating the previously reported myopathy associated with pathogenic SPTBN4 variants is neurogenic in origin. More broadly, we show that α2, ß1 and ß2 spectrins are found in skeletal muscle, with α2 and ß1 spectrins being enriched at the postsynaptic neuromuscular junction (NMJ). Surprisingly, using muscle specific conditional knockout mice, we show that loss of α2 and ß2 spectrins had no effect on muscle health, function or the enrichment of ß1 spectrin at the NMJ. Muscle specific deletion of ß1 spectrin also had no effect on muscle health, but, with increasing age, resulted in the loss of clustered NMJ Na+ channels. Together, our results suggest that muscle ß1 spectrin functions independently of an associated α spectrin to maintain Na+ channel clustering at the postsynaptic NMJ. Furthermore, despite repeated exposure to strong forces and in contrast to neurons, muscles do not require spectrin cytoskeletons to maintain cell shape or integrity. KEY POINTS: The myopathy found in pathogenic human SPTBN4 variants (where SPTBN4 is the gene encoding ß4 spectrin) is neurogenic in origin. ß1 spectrin plays essential roles in maintaining the density of neuromuscular junction Nav1.4 Na+ channels. By contrast to the canonical view of spectrin organization and function, we show that ß1 spectrin can function independently of an associated α spectrin. Despite the large mechanical forces experienced by muscle, we show that spectrins are not required for muscle cell integrity. This is in stark contrast to red blood cells and the axons of neurons.


Assuntos
Junção Neuromuscular , Canais de Sódio , Espectrina , Animais , Humanos , Camundongos , Citoesqueleto de Actina/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares , Junção Neuromuscular/metabolismo , Espectrina/genética , Espectrina/análise , Espectrina/metabolismo , Canais de Sódio/metabolismo
4.
J Peripher Nerv Syst ; 29(1): 88-96, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37989721

RESUMO

BACKGROUND AND AIMS: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. METHODS: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. RESULTS: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. INTERPRETATION: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.


Assuntos
Neuralgia , Proteômica , Humanos , Neuralgia/etiologia , Proteínas , Plasma
5.
Support Care Cancer ; 32(2): 117, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38244122

RESUMO

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.


Assuntos
Antineoplásicos , Sobreviventes de Câncer , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Antineoplásicos/efeitos adversos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/tratamento farmacológico , Pessoal Administrativo
6.
J Neurol Neurosurg Psychiatry ; 94(11): 962-972, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37015772

RESUMO

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.


Assuntos
Antineoplásicos , Doenças Neurodegenerativas , Síndromes Neurotóxicas , Humanos , Axônios/patologia , Síndromes Neurotóxicas/etiologia , Doenças Neurodegenerativas/patologia , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo
7.
Clin Infect Dis ; 74(3): 427-436, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33956972

RESUMO

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.


Assuntos
Doenças Autoimunes , COVID-19 , Doenças Autoimunes/epidemiologia , Teste para COVID-19 , Humanos , Pandemias , Fatores de Risco , SARS-CoV-2
8.
J Peripher Nerv Syst ; 27(1): 31-37, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34931740

RESUMO

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP). We included 261 patients enrolled in the Peripheral Neuropathy Research Registry who had a complete dataset including a plasma vitamin B6 value. Patients with vitamin B6 deficiency (0-4.9 µg/L) were excluded. We performed a chi-square test for independence and analyzed the logistic relation of elevated plasma B6 level to nerve conduction studies (NCS), neurological examination findings, and patient-reported symptoms controlling for age and time elapsed since neuropathy symptom onset. Plasma B6 level was not related to neuropathy severity. There was no logistic relation of elevated plasma B6 level to NCS results, examination features including toe strength, vibration sense, and deep tendon reflexes, or patient-reported numbness or pain intensity. This study suggests that moderately elevated plasma B6 levels, even in the 100 to 200 µg/L range, are not associated with significantly worse neuropathy signs or symptoms. Although standard supplementation of B6 does not appear to have a major negative affect on CIAP, this study does not directly answer whether stopping supplementation will have a beneficial effect. Very few patients in the study had vitamin B6 levels >300 µg/L, suggesting that screening for vitamin B6 toxicity may be left to the discretion of the physician.


Assuntos
Doenças do Sistema Nervoso Periférico , Polineuropatias , Estudos de Coortes , Humanos , Doenças do Sistema Nervoso Periférico/complicações , Polineuropatias/diagnóstico , Polineuropatias/etiologia , Piridoxina , Vitamina B 6
9.
J Peripher Nerv Syst ; 27(1): 58-66, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35137510

RESUMO

Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice. CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1-/- mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were evaluated histologically. Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, genetic deletion of SARM1 conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout. Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in C3-PMP CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.


Assuntos
Doença de Charcot-Marie-Tooth , Doenças Desmielinizantes , Animais , Proteínas do Domínio Armadillo/genética , Proteínas do Citoesqueleto/genética , Doenças Desmielinizantes/genética , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Bainha de Mielina/patologia , Fenótipo
10.
J Peripher Nerv Syst ; 26 Suppl 2: S11-S20, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34768313

RESUMO

Normal nerve architecture is basic to a complete understanding of nerve pathology. Here, normal components of the nerve are illustrated, including myelinated and non-myelinated nerve fibres, stromal elements, and vascular components. These are relevant because the differential diagnosis of neuropathy depends on the pathological processes affecting axon, myelin, interstitial space, and blood vessels. Thus, we present a description of the general pathological characteristics for the diagnosis of peripheral nerve disorders.


Assuntos
Doenças do Sistema Nervoso Periférico , Axônios/patologia , Humanos , Bainha de Mielina/patologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/patologia
11.
Glia ; 68(1): 161-177, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31453649

RESUMO

Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1 f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/- , MCT1 f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, reduced mechanical sensitivity is evident in aged P0-Cre+/- , MCT1 f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein, and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the contribution of SC MCT1 to both SC metabolism and peripheral nerve maturation and aging.


Assuntos
Envelhecimento/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Bainha de Mielina/metabolismo , Células de Schwann/metabolismo , Células Receptoras Sensoriais/metabolismo , Simportadores/metabolismo , Envelhecimento/genética , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Transportadores de Ácidos Monocarboxílicos/deficiência , Transportadores de Ácidos Monocarboxílicos/genética , Bainha de Mielina/genética , Condução Nervosa/fisiologia , Nervo Sural/metabolismo , Simportadores/deficiência , Simportadores/genética
12.
J Peripher Nerv Syst ; 25(4): 388-394, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33025680

RESUMO

Although exercise is associated with better outcomes in patients with some peripheral neuropathies, data in idiopathic peripheral neuropathies is lacking. This study was completed to do a comprehensive data analysis about the benefits of regular exercise in a well-characterized cohort of patients with idiopathic distal, symmetrical, axonal polyneuropathy enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine. From the patient-reported exercise habits, metabolic equivalents (METs) were calculated and the patient information was grouped into four categories. The PNRR data set, including patient reported pain, numbness, and weakness, was analyzed using the METs categories to evaluate for the benefits of exercise. We controlled for the components of metabolic syndrome including Hemoglobin A1c (HbA1c), systolic and diastolic blood pressure (BP), high density lipids (HDL) and triglyceride level, and body mass index (BMI) as defined by the Adult Treatment Panel III Guidelines. Lower METs were associated with neuropathic pain, but not with other peripheral neuropathy symptoms. Patients with IPN who exercised were less likely to have painful neuropathy independent of the average METs per week (P < .01). No significant differences were seen for patient reported numbness, weakness, or balance issues. The data suggests that patients with idiopathic neuropathy benefit from exercises even if performed on a low intensity level or less frequently, and patients are less likely to have severe pain symptoms when exercising on a regular basis.


Assuntos
Exercício Físico/fisiologia , Neuralgia/fisiopatologia , Polineuropatias/fisiopatologia , Sistema de Registros , Adulto , Idoso , Pressão Sanguínea/fisiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Neuralgia/etiologia , Polineuropatias/complicações
13.
Mol Ther ; 27(2): 411-423, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30611662

RESUMO

The loss of oligodendrocytes (OLs) and subsequently myelin sheaths following injuries or pathologies in the CNS leads to debilitating functional deficits. Unfortunately, effective methods of remyelination remain limited. Here, we present a scaffolding system that enables sustained non-viral delivery of microRNAs (miRs) to direct OL differentiation, maturation, and myelination. We show that miR-219/miR-338 promoted primary rat OL differentiation and myelination in vitro. Using spinal cord injury as a proof-of-concept, we further demonstrate that miR-219/miR-338 could also be delivered non-virally in vivo using an aligned fiber-hydrogel scaffold to enhance remyelination after a hemi-incision injury at C5 level of Sprague-Dawley rats. Specifically, miR-219/miR-338 mimics were incorporated as complexes with the carrier, TransIT-TKO (TKO), together with neurotrophin-3 (NT-3) within hybrid scaffolds that comprised poly(caprolactone-co-ethyl ethylene phosphate) (PCLEEP)-aligned fibers and collagen hydrogel. After 1, 2, and 4 weeks post-treatment, animals that received NT-3 and miR-219/miR-338 treatment preserved a higher number of Olig2+ oligodendroglial lineage cells as compared with those treated with NT-3 and negative scrambled miRs (Neg miRs; p < 0.001). Additionally, miR-219/miR-338 increased the rate and extent of differentiation of OLs. At the host-implant interface, more compact myelin sheaths were observed when animals received miR-219/miR-338. Similarly within the scaffolds, miR-219/miR-338 samples contained significantly more myelin basic protein (MBP) signals (p < 0.01) and higher myelination index (p < 0.05) than Neg miR samples. These findings highlight the potential of this platform to promote remyelination within the CNS.


Assuntos
Sistema Nervoso Central/metabolismo , Portadores de Fármacos/química , MicroRNAs/metabolismo , Remielinização/fisiologia , Animais , Feminino , Hidrogéis/química , Imuno-Histoquímica , MicroRNAs/química , MicroRNAs/genética , Microscopia Eletrônica de Varredura , Fatores de Crescimento Neural/metabolismo , Ratos , Ratos Sprague-Dawley , Remielinização/genética
14.
Ann Neurol ; 93(2): 220-221, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36468201
15.
Muscle Nerve ; 60(4): 437-442, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325319

RESUMO

BACKGROUND: Reliable measurement of functional recovery is critical in translational peripheral nerve regeneration research. Behavioral functional assessments such as volitional grip strength testing (vGST) are limited by inherent behavioral variability. Isometric tetanic force testing (ITFT) is highly reliable but precludes serial measurements. Combining elements of vGST and ITFT, stimulated grip strength testing (sGST) involves percutaneous median nerve stimulation to elicit maximal tetanic contraction of digital flexors, thereby allowing for consistent measurement of maximal grip strength. METHODS: We measured side-to-side equivalence of force using sGST, vGST, and ITFT to determine relative reliability and repeatability. We also performed weekly force measurements following median nerve repair. RESULTS: sGST demonstrated greater reliability and inter-trial repeatability than vGST and similar reliability to ITFT, with the added benefit of serial measurements. CONCLUSIONS: sGST is a valid method for assessing functional recovery that addresses the limitations of the currently available modalities used in translational peripheral nerve regeneration research.


Assuntos
Força da Mão/fisiologia , Contração Isométrica/fisiologia , Nervo Mediano/fisiopatologia , Regeneração Nervosa , Recuperação de Função Fisiológica , Animais , Comportamento Animal , Estimulação Elétrica , Masculino , Nervo Mediano/lesões , Nervo Mediano/fisiologia , Nervo Mediano/cirurgia , Ratos , Ratos Endogâmicos Lew , Reprodutibilidade dos Testes , Nervo Ulnar/cirurgia
16.
J Peripher Nerv Syst ; 24(1): 39-47, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30629307

RESUMO

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus-, and chemotherapy-induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi-center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease-altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted-omics methodologies.


Assuntos
Protocolos Clínicos , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/etiologia , Estudos Prospectivos , Adulto Jovem
18.
EMBO J ; 33(23): 2798-813, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25349190

RESUMO

Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals.


Assuntos
Encéfalo/metabolismo , Dinaminas/metabolismo , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Miócitos Cardíacos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Dinaminas/genética , Tomografia com Microscopia Eletrônica , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Cadeias Pesadas de Miosina/genética , Ubiquitinação
19.
Muscle Nerve ; 55(6): 894-901, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27464347

RESUMO

INTRODUCTION: Age-associated muscle strength decline is a major contributing factor to increased late-life functional decline and comorbidity, and is strongly associated with early mortality. Although all parts of the neuromuscular system seem to be affected by aging, dying-back of motor axons likely plays a major role. METHODS: We compared the degeneration in ventral roots and neuromuscular junction denervation in young and aged mice and correlated the findings with strength and electrophysiological measures. RESULTS: With normal aging, there is little decline in motor axon numbers in the ventral roots, but the neuromuscular junctions show marked partial denervation that is associated with increased jitter on stimulated single fiber electromyography and a decrease in muscle strength. CONCLUSIONS: These findings suggest that dying-back axonal degeneration may be partially responsible for the electrophysiological and strength changes observed with aging. Muscle Nerve 55: 894-901, 2017.


Assuntos
Envelhecimento , Axônios/patologia , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Animais , Eletromiografia , Camundongos , Camundongos Endogâmicos C57BL , Placa Motora/patologia , Denervação Muscular , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Terminações Pré-Sinápticas/patologia , Raízes Nervosas Espinhais/patologia , Tubulina (Proteína)/metabolismo
20.
J Peripher Nerv Syst ; 22(3): 162-171, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28485482

RESUMO

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development.


Assuntos
Proteínas do Domínio Armadillo/deficiência , Proteínas do Citoesqueleto/deficiência , Dieta Hiperlipídica/efeitos adversos , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/prevenção & controle , Potenciais de Ação/genética , Análise de Variância , Animais , Antineoplásicos Fitogênicos/toxicidade , Proteínas do Domínio Armadillo/genética , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Hiperalgesia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Condução Nervosa/genética , Paclitaxel/toxicidade , Limiar da Dor/fisiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Tempo de Reação/genética , Nervo Sural/patologia
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