Pathogenesis Of Peripheral Neuropathy Research Articles

High-intensity interval training, caloric restriction, or their combination have beneficial effects on metabolically acquired peripheral neuropathy.

Peripheral neuropathy (PN) is a prevalent and debilitating complication of obesity, prediabetes, and type 2 diabetes, which remains poorly understood and lacks disease-modifying therapies. Fortunately, diet and/or exercise have emerged as effective treatment strategies for PN. Here, we examined the impact of caloric restriction (CR) and high-intensity interval training (HIIT) interventions, alone or combined (HIIT-CR), on metabolic and PN outcomes in high-fat diet (HFD) mice. HFD feeding alone resulted in obesity, impaired glucose tolerance, and PN. Peripheral nerves isolated from these mice also developed insulin resistance (IR). CR and HIITCR, but not HIIT alone, improved HFD-induced metabolic dysfunction. However, all interventions improved PN to similar extents. When examining the underlying neuroprotective mechanisms in whole nerve, we found that CR and HIIT-CR activate the fuel-sensing enzyme AMP-activated protein kinase (AMPK). We then performed complimentary in vitro work in Schwann cells, the glia of peripheral nerve. Treating primary Schwann cells with the saturated fatty acid palmitate to mimic prediabetic conditions caused IR, which was reversed by the AMPK activator, AICAR. Together, these results enhance our understanding of PN pathogenesis, the differential mechanisms by which diet and exercise may improve PN, and Schwann cell-specific contributions to nerve insulin signaling and PN progression.

The Morbid Impact of Environmental Toxins on the Human Nervous System: Peripheral Neuropathy Nexus with Organic Solvents, Pesticides, and Heavy Metals

Peripheral neuropathy is a complex disorder characterized by damage to the peripheral nerves, resulting in various sensory, motor, and autonomic symptoms. This review offers a detailed examination of peripheral neuropathy, covering its prevalence, effects on individuals and society, causes, diagnosis, mechanisms, treatment, and management, focusing on its association with environmental toxins. The etiology of peripheral neuropathy is multifactorial, encompassing diverse causes such as diabetes mellitus, autoimmune diseases, infections, vitamin deficiencies, toxic exposures, and genetic factors. Notably, environmental toxins, including organic solvents, pesticides, and heavy metals, have been implicated in the pathogenesis of peripheral neuropathy. Environmental toxins exert their neurotoxic effects through various mechanisms, including disruption of neuronal membrane integrity, interference with neurotransmission, induction of oxidative stress, and promotion of inflammatory responses. Accurate diagnosis of peripheral neuropathy involves a comprehensive medical history, neurological examination, electrophysiological studies, imaging tests, and laboratory investigations to identify underlying causes, including environmental toxin exposure. Treatment strategies for environmental toxin-induced peripheral neuropathy focus on eliminating exposure, managing symptoms, and preventing further nerve damage. Pharmacological interventions, adjunctive therapies, nutritional support, regular monitoring, and patient education are integral to management. A multidisciplinary approach is fundamental for diagnosing and managing peripheral neuropathy effectively, emphasizing identifying and mitigating environmental toxin exposure to alleviate symptoms and improve quality of life.

Exploring causal correlations between plasma proteins and peripheral neuropathy: a Mendelian randomization.

Peripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies. To identify potential therapeutic targets for PN, we employed two-sample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genome-wide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify protein-PN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on drug-gene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN. Through MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN. Mendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN.

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

Crosstalk of Mast Cells and Natural Killer Cells with Neurons in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major comorbidity of cancer. Multiple clinical interventions have been studied to effectively treat CIPN, but the results have been disappointing, with no or little efficacy. Hence, understanding the pathophysiology of CIPN is critical to improving the quality of life and clinical outcomes of cancer patients. Although various mechanisms of CIPN have been described in neuropathic anti-cancer agents, the neuroinflammatory process involving cytotoxic/proinflammatory immune cells remains underexamined. While mast cells (MCs) and natural killer (NK) cells are the key innate immune compartments implicated in the pathogenesis of peripheral neuropathy, their role in CIPN has remained under-appreciated. Moreover, the biology of proinflammatory cytokines associated with MCs and NK cells in CIPN is particularly under-evaluated. In this review, we will focus on the interactions between MCs, NK cells, and neuronal structure and their communications via proinflammatory cytokines, including TNFα, IL-1β, and IL-6, in peripheral neuropathy in association with tumor immunology. This review will help lay the foundation to investigate MCs, NK cells, and cytokines to advance future therapeutic strategies for CIPN.

A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy.

As the prevalence of prediabetes and type 2 diabetes (T2D) continues to increase worldwide, accompanying complications are also on the rise. The most prevalent complication, peripheral neuropathy (PN), is a complex process which remains incompletely understood. Dyslipidemia is an emerging risk factor for PN in both prediabetes and T2D, suggesting that excess lipids damage peripheral nerves; however, the precise lipid changes that contribute to PN are unknown. To identify specific lipid changes associated with PN, we conducted an untargeted lipidomics analysis comparing the effect of high-fat diet (HFD) feeding on lipids in the plasma, liver, and peripheral nerve from three strains of mice (BL6, BTBR, and BKS). HFD feeding triggered distinct strain- and tissue-specific lipid changes, which correlated with PN in BL6 mice versus less robust murine models of metabolic dysfunction and PN (BTBR and BKS mice). The BL6 mice showed significant changes in neutral lipids, phospholipids, lysophospholipids, and plasmalogens within the nerve. Sphingomyelin (SM) and lysophosphatidylethanolamine (LPE) were two lipid species that were unique to HFD BL6 sciatic nerve compared to other strains (BTBR and BKS). Plasma and liver lipids were significantly altered in all murine strains fed a HFD independent of PN status, suggesting that nerve-specific lipid changes contribute to PN pathogenesis. Many of the identified lipids affect mitochondrial function and mitochondrial bioenergetics, which were significantly impaired in ex vivo sural nerve and dorsal root ganglion sensory neurons. Collectively, our data show that consuming a HFD dysregulates the nerve lipidome and mitochondrial function, which may contribute to PN in prediabetes.

A Role for Fatty Acids in Peripheral Neuropathy Associated with Type 2 Diabetes and Prediabetes.

Significance: As the global prevalence of diabetes rises, diabetic complications are also increasing at an alarming rate. Peripheral neuropathy (PN) is the most prevalent complication of diabetes and prediabetes, and is characterized by progressive sensory loss resulting from nerve damage. While hyperglycemia is the major risk factor for PN in type 1 diabetes (T1D), the metabolic syndrome (MetS) underlies the onset and progression of PN in type 2 diabetes (T2D) and prediabetes. Recent Advances: Recent reports show that dyslipidemia, a MetS component, is strongly associated with PN in T2D and prediabetes. Dyslipidemia is characterized by an abnormal plasma lipid profile with uncontrolled lipid levels, and both clinical and preclinical studies implicate a role for dietary fatty acids (FAs) in PN pathogenesis. Molecular studies further show that saturated and unsaturated FAs differentially regulate the nerve lipid profile and nerve function. Critical Issues: We first review the properties of FAs and the neuroanatomy of the peripheral nervous system (PNS). Second, we discuss clinical and preclinical studies that implicate the involvement of FAs in PN. Third, we summarize the potential effects of FAs on nerve function and lipid metabolism within the peripheral nerves, sensory neurons, and Schwann cells. Future Directions: Future directions will focus on identifying molecular pathways in T2D and prediabetes that are modulated by FAs in PN. Determining pathophysiological mechanisms that underlie the injurious effects of saturated FAs and beneficial properties of unsaturated FAs will provide mechanistic targets for developing new targeted therapies to treat PN associated with T2D and prediabetes. Antioxid. Redox Signal. 37, 560-577.

Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19.

Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.

Quality Control Mechanisms of Mitochondria: Another Important Target for Treatment of Peripheral Neuropathy.

Mitochondria provide energy for various cellular activities and are involved in the regulating of several physiological and pathological processes. Mitochondria constitute a dynamic network regulated by numerous quality control mechanisms; for example, division is necessary for mitochondria to develop, and fusion dilutes toxins produced by the mitochondria. Mitophagy removes damaged mitochondria. The etiologies of peripheral neuropathy include congenital and acquired diseases, and the pathogenesis varies; however, oxidative stress caused by mitochondrial damage is the accepted pathogenesis of peripheral neuropathy. Regulation and control of mitochondrial quality might point the way toward potential treatments for peripheral neuropathy. This article will review mitochondrial quality control mechanisms, their involvement in peripheral nerve diseases, and their potential therapeutic role.

Clinical Manifestations, Pathogenesis, Diagnosis and Treatment of Peripheral Neuropathies in Connective Tissue Diseases: More Diverse and Frequent in Different Subtypes than Expected.

Purpose of review: To discuss and summarize recent findings in peripheral neuropathy (PN) related to connective tissue diseases (CTD) including its prevalence, clinical manifestations, pathogenesis, diagnosis and treatment. Recent findings: Although PN is a common complication in CTD and has been well studied, recent research has shown that PN is more diverse and frequent in different subtypes of CTD than was expected. The incidence of PN in Sjögren’s syndrome and rheumatoid arthritis (RA) varies according to different disease subtypes, and the pathogenesis of neuropathic pain in different subtypes of eosinophilic granulomatosis with polyangiitis (EGPA) may also differ. Neurogenic inflammation, autoantibody-mediated changes, ischemia of the vascular wall and metabolic mechanisms have been shown to contribute to the pathogenesis of PN in CTD. Moreover, allergic inflammation has been recently identified as a possible new mechanism producing peripheral neuropathic pain associated with MPO-ANCA negative EGPA patients. Glucocorticoids are routinely used to relieve pain caused by PN. However, these steroids may cause hyperalgesia, exacerbate neuropathic pain, and activate the early phase of pain induction and produce hyperalgesia. Recently, neuroactive steroids, such as progesterone, tetrahydroprogesterone and testosterone, have been shown to exert protective effects for several PN symptoms, and in particular neuropathic pain. Neuroactive steroids will be an interesting topic for future research into PN in CTD. Summary: It is essential for the diagnosis and treatment of PN in CTD to be updated. Timely diagnosis, appropriate treatments, and multidisciplinary care are essential to minimize morbidity and decrease the risk of permanent neurologic deficits. Further studies are needed to guide diagnosis and treatment.

Peripheral Nerve Development and the Pathogenesis of Peripheral Neuropathy: the Sorting Point.

Nerve development requires a coordinated sequence of events and steps to be accomplished for the generation of functional peripheral nerves to convey sensory and motor signals. Any abnormality during development may result in pathological structure and function of the nerve, which evolves in peripheral neuropathy. In this review, we will briefly describe different steps of nerve development while we will mostly focus on the molecular mechanisms involved in radial sorting of axons, one of these nerve developmental steps. We will summarize current knowledge of molecular pathways so far reported in radial sorting and their possible interactions. Finally, we will describe how disruption of these pathways may result in human neuropathies.

High Dietary Fat Consumption Impairs Axonal Mitochondrial Function In Vivo.

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia in vitro demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis in vivo We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca2+ levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca2+ levels and impairs impulse conduction within the saphenous nerve in prediabetic PN.SIGNIFICANCE STATEMENT Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system in vivo is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia in vivo.

Early diagnosis and treatment of diabetic and alcoholic polyneuropathy in outpatient practice

Diabetes mellitus (DM) and chronic alcoholism (CA) are diseases that damage many organs and systems of the body and, in particular, lead to peripheral neuropathies. The pathogenesis of peripheral neuropathies caused by diabetes mellitus (DM) and CA is complex and diverse. Different types of peripheral neuropathies develop according to the leading pathogenetic mechanism. The most common type of peripheral neuropathy in DM is diabetic distal symmetric polyneuropathy (DSPN) and that in CA is alcoholic polyneuropathy (APN). The principles of diagnosis and treatment of DSPN and APN are considered. Treatment of DSPN and APN is complex, which is aimed at treating the underlying disease and includes non-drug and drug treatments. The mainstay of DSPN treatment is achievement of the optimal blood glucose level, maintenance of a healthy lifestyle (diet, daily activity), and correction of cardiovascular comorbidities (if any) with symptomatic pharmacotherapy for neuropathic pain (if any) with antidepressants or anticonvulsants. Antioxidants, such as B group vitamins (B1, B6 and B12) and alpha-lipoic acid (ALA), are widely used to treat DSPN in clinical practice. APN treatment involves cessation of alcohol consumption, physical and mental rehabilitation, and intake of B group vitamins (B1, B2, B6 and B12). The use of ALA in DSPN and APN is discussed.

The Role of Oxidative Stress in Peripheral Neuropathy.

Peripheral neuropathy (PN) is a common disease affecting about 5% of the general population after the age of 50. Causes of PN are numerous and include genetic, diabetes, alcohol, vitamin deficiencies, and gluten sensitivity among others. This systematic review aimed to study the association between oxidative stress and PN in an attempt to better understand PN pathogenesis. A computer-based, systematic search was conducted on the PubMed database, and ensuing data from included articles was analyzed and discussed in this review. Sixty-nine papers were eligible and were used for this review. Peripheral neuropathy is associated with an increase of reactive oxygen species and a decrease in endogenous antioxidants. Genetic predisposition to oxidative damage may be a factor. Antioxidant treatment is promising regarding treatment. Though further research is necessary to better understand the underlying mechanism, it is evident that oxidative stress is implicated in the pathogenesis of - or is at least systematically present in - PN.

First person – Phillipe O'Brien, Kai Guo, Stephanie Eid, Amy Rumora and Lucy Hinder

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms (DMM), helping early-career researchers promote themselves alongside their papers. Phillipe O'Brien, Kai Guo, Stephanie Eid, Amy Rumora and Lucy Hinder are first authors on ‘Integrated lipidomic and transcriptomic analyses identify altered nerve triglycerides in mouse models of prediabetes and type 2 diabetes’, published in DMM. Phillipe, Stephanie, Amy and Lucy are all postdoctoral researchers in the lab of Eva L. Feldman at the University of Michigan, MI, USA, investigating the pathogenesis of peripheral neuropathy using mouse models of obesity and diabetes. Kai is a postdoctoral researcher in the lab of Junguk Hur at the University of North Dakota, Grand Forks, ND, USA, and uses high-throughput genomic data analysis to understand the development of neurological disorders.

The role of dietary non-heme iron load and peripheral nerve inflammation in the development of peripheral neuropathy (PN) in obese non-diabetic leptin-deficient ob/ob mice

ABSTRACTIntroduction: Here, we investigated inflammatory signs of peripheral nerves in leptin-deficient obese ob/ob mice and the modulating effects of the exogenous iron load.Methods: Ob/ob and ob/+ control mice were fed with high, standard, or low iron diet for four months.Results: We found intraepidermal nerve fiber degeneration in foot skin and low-grade neuropathic abnormalities including mildly slowed motor and compound sensory nerve conduction velocities and low-grade macrophage and T-cell infiltration without overt neuropathology in sciatic nerves of all ob/ob mice. Low dietary iron load caused more pronounced abnormalities than high iron load in ob/ob mice.Discussion: Our data suggest that dietary non-heme iron deficiency may be a modulating factor in the pathogenesis of peripheral neuropathy in obese ob/ob mice with metabolic syndrome. Once the mechanisms can be further elucidated, how low dietary iron augments peripheral nerve degeneration and dysfunction via pro-inflammatory pathways and new therapeutic strategies could be developed.Abbreviations: CMAP: compound muscle action potential; cSNCV: compound sensory nerve conduction velocity; IENFD: intraepidermal nerve fiber density; LDL: low-density lipoprotein; MetS: metabolic syndrome; MNCV: motor conduction velocity; NCV: nerve conduction velocity; PN: peripheral neuropathy; PNS: peripheral nervous system; STZ: streptozotocin; T2D: type 2 diabetes mellitus; TNF alpha: tumor necrosis factor alpha; WHO: World Health Organization

Tissue plasminogen activator and neuropathy open the blood-nerve barrier with upregulation of microRNA-155-5p in male rats

The blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels is sealed by tight junction proteins. BNB alterations are a crucial factor in the pathogenesis of peripheral neuropathies. However, barrier opening, e.g. by tissue plasminogen activator (tPA), can also facilitate topical application of analgesics. Here, we examined tPA both in the pathophysiology of neuropathy-induced BNB opening or via exogenous application and its effect on the cytoplasmatic tight junction protein anchoring protein, zona occludens-1 (ZO-1), the adherens molecule JAM-C and microRNA(miR)-155-5p. Specifically, we investigated whether tPA alone and barrier opening lead to pain behavioral changes, i.e. hyperalgesia, or whether these effects require further factors.Male Wistar rats underwent chronic constriction injury (CCI) or were treated by a single perisciatic application of recombinant (r)tPA. CCI elicited mechanical allodynia, tPA mRNA upregulation, macrophage invasion, BNB leakage for large molecule tracers, downregulation of ZO-1 and JAM-C mRNA/protein, and a loss of immunoreactivity of both in perineurium and endoneurial cells. Similarly, after perisciatic rtPA injection, ZO-1 and JAM-C mRNA as well as cytosolic/membrane protein and ZO-1 immunoreactivity were downregulated, and the BNB was opened. Neither mechanical hypersensitivity nor macrophage infiltration was observed after rtPA in contrast to CCI. Mechanistically, miR-155-5p, which is known to destabilize barriers and tight junction proteins like claudin-1 and ZO-1, was increased in CCI and to lesser extent after rtPA application. In summary, tPA transiently opens the BNB possibly via miR-155-5p. However, tPA does not provoke allodynia in the absence of a neuropathic stimulus like a ligation or inflammation.

Role of the cystathionine γ-lyase/H<sub>2</sub>S pathway in paclitaxel-induced HMGB1 release from macrophages and its impact on the pathogenesis of peripheral neuropathy in mice

Role of the cystathionine γ-lyase/H<sub>2</sub>S pathway in paclitaxel-induced HMGB1 release from macrophages and its impact on the pathogenesis of peripheral neuropathy in mice

DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.

DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 that we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive. Here, we show that Dhtkd1-/- mice mimic the major aspects of CMT2 phenotypes, characterized by progressive weakness and atrophy in the distal parts of limbs with motor and sensory dysfunctions, which are accompanied with decreased nerve conduction velocity. Moreover, DHTKD1 deficiency causes severe metabolic abnormalities and dramatically increased levels of 2-ketoadipic acid (2-KAA) and 2-aminoadipic acid (2-AAA) in urine. Further studies revealed that both 2-KAA and 2-AAA could stimulate insulin biosynthesis and secretion. Subsequently, elevated insulin regulates myelin protein zero (Mpz) transcription in Schwann cells via upregulating the expression of early growth response 2 (Egr2), leading to myelin structure damage and axonal degeneration. Finally, 2-AAA-fed mice do reproduce phenotypes similar to CMT2Q phenotypes. In conclusion, we have demonstrated that loss of DHTKD1 causes CMT2Q-like phenotypes through dysregulation of Mpz mRNA and protein zero (P0) which are closely associated with elevated DHTKD1 substrate and insulin levels. These findings further indicate an important role of metabolic disorders in addition to mitochondrial insufficiency in the pathogenesis of peripheral neuropathies.

Toll-Like Receptors 2/4 and Diabetic Peripheral Neuropathy

Peripheral neuropathy (PN) is a common, morbid complication of diabetes and prediabetes. Dysfunction of toll like receptors (TLR) 2 and 4 has been implicated in PN pathogenesis, and blocking TLR4 is proposed as a treatment for neuropathic pain. WT and TLR 2/4 global KO (TLR2/4-/-; n=5) mice were placed on a 60% high fat diet (HFD, n=5), with 5 WT controls provided a standard diet (CON, n=5). Mice underwent metabolic, neuropathic, and immunological phenotyping (Table 1) at early and late disease time points. TLR2/4-/- mice weighed more (P ≤ 0.023) but did not have increased fasting blood glucose levels. They had reduced hind paw withdrawal latencies (HPL) compared to HFD mice (P ≤ 0.01) and were similar to CON in early disease, but worsened in later disease. TLR2/4-/- mice consistently had lower sural nerve conduction velocities than CON and worsened as disease progressed (P ≤ 0.048). Immunophenotyping during late disease showed differences in the number of peripheral blood Ly6C- myeloid cells (P ≤ 0.05) and F4/80+ expression (P ≤ 0.0001). Inflammatory profiles of the sural nerve indicated a lower gene expression of the chemoattractant CCL-12 chemokine in TLR2/4-/- compared to CON mice. These results suggest that TLR2/4 KO may be initially protective against HFD induced neuropathy, but as PN progresses this effect is lost. Differences in circulating immune cells and CCL-12 gene expression may indicate an anti-inflammatory phenotype in TLR2/4-/- mice.Table 1. Metabolic, neuropathic and immunological phenotyping.Phenotypic MetricCON (n=5)HFD (n=5)TLR2/4-/-(n=5)Late stage weight (g)26 ± 339 ± 351 ± 3Late stage fasting blood glucose (mg/dL)150 ± 22190 ± 22172 ± 22HPL (sec)Early: 3.6 ± 0.3Late: 3.5 ± 0.4Early: 5.7 ± 0.3Late: 5.5 ± 0.4Early: 4.4 ± 0.3Late: 6.1 ± 0.4Sural NCV (m/s)Early: 22.0 ± 0.7Late: 23.9 ± 0.7Early: 18.5 ± 0.7Late: 17.9 ± 0.7Early: 20.0 ± 0.7Late: 17.2 ± 0.9Late stage Ly6C- circulating myeloid cells (104 cells/mL)7.8 ± 2.614.0 ± 2.74.8 ± 2.7Late stage circulating myeloid F4/80 expression (mean florescent intensity)978 ± 9611383 ± 10199967 ± 1019Late stage CCL-12 sural nerve gene expression (relative quantity)1.16 ± 0.240.59 ± 0.280.32 ± 0.24 Disclosure S. Elzinga: None. B. Murdock: None. J.M. Hayes: None. M.A. Tabbey: None. E.L. Feldman: None.