Impaired peripheral nerve regeneration in diabetes mellitus

Kennedy, James; Zochodne, Douglas W.

doi:10.1111/j.1085-9489.2005.0010205.x

Cited by 164 publications

(111 citation statements)

References 130 publications

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“…These results are particularly relevant for diabetic neuropathy where it is believed that reparative responses occur in response to continual nerve damage (48). As sirtuin activity is clearly associated with cellular metabolism, and sirtuin activity is often deregulated in diabetes (49), a role for aberrant Sirt2 activity in impaired SC plasticity during nerve regeneration in diabetes is plausible (5)(6)(7)(8)50). Accordingly, the Sirt2/Par-3/aPKC pathway is a potential therapeutic target for treatment of neuropathy associated with altered metabolic conditions.…”

Section: Discussionmentioning

confidence: 99%

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Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Beirowski¹,

Gustin

Armour

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

151

119

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The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD + -dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.neuropathy | sirtuin | acetylation M yelinating Schwann cells (SCs) perform a range of tasks required for correct function of the peripheral nervous system (PNS). In addition to ensuring normal locomotion and sensation and providing trophic support of axons (1), they control regenerative and reparative responses in peripheral nerves (2). These functions are tightly linked to the ability of differentiated SCs to intimately associate with axons and ensheath them with compact myelin. Various pathways in SCs have been identified that are crucial for this process including neuronal growth factors, cell adhesion, and a number of second messenger systems (3). These pathways are interrelated with strict temporal control of key transcription factors, collectively responsible for up-regulation of genes critical for structural assembly of myelin (3, 4).Metabolic derangements contribute to a major class of conditions in which SC function is impaired. For example, numerous studies indicate that nerve regeneration and myelination after injury are impaired in diabetic neuropathy (5-8). Moreover, SC myelination can be altered by changes in nutrition (9, 10). These findings give rise to the idea that abnormal metabolic conditions could lead to aberrant myelination via abnormalities in SC function. We previously identified Sir-two-homolog 2 (Sirt2) in gene expression profiling experiments as a putative myelinationassociated protein on the basis of the similarity of its expression to that of mRNAs encoding structural myelin proteins during periods of myelin formation (11). Sirt2 is a member of the conserved sirtuin family of NAD + -dependent deacetylases that modulate cellular processes in accord with the metabolic state (12, 13). Depending on the cellular context and tissue type, Sirt2 is reported to deacetylate α-tubulin (14, 15), control cell division (16), regulate adipocyte differentiation through FOXO1 (17), and alter gene expression via the deacetylation of histone H4 (18) among other functions.Here, we demonstrate that norm...

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Section: Discussionmentioning

confidence: 99%

“…For example, numerous studies indicate that nerve regeneration and myelination after injury are impaired in diabetic neuropathy (5)(6)(7)(8). Moreover, SC myelination can be altered by changes in nutrition (9,10).…”

mentioning

confidence: 99%

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Beirowski¹,

Gustin

Armour

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

151

119

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“…However, to be effective it should be instituted at an early stage since, as is the case with other late complications of diabetes, the late phases of diabetic neuropathy are poorly reversible or even irreversible. Moreover, ample evidence of defective nerve regeneration in DM is available [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Advanced Diabetic Neuropathy: A Point of no Return?

Bouc̆ek¹

2006

Rev Diabetic Stud

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■ AbstractDiabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel noninvasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects.

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“…Diabetes 57:181-189, 2008 A xonal regeneration is defective in both experimental (1,2) and clinical (3,4) diabetic neuropathy. This may be instrumental in the pathogenesis of diabetic neuropathy, but its mechanism is unclear and multifactorial-a combination of oxidative and biochemical stress, neurotrophin deficits, impaired synthesis and transport of cytoskeletal components, and formation of intracellular and extracellular advanced glycation end products (5)(6)(7) Neurotrophins play an important role in promoting neuronal survival, differentiation, function, and repair. It is well established that they regulate axonal growth in sensory neurons, both regenerative growth in response to injury and collateral sprouting of uninjured nerve terminals (8 -11).…”

mentioning

confidence: 99%

Neuritin Mediates Nerve Growth Factor–Induced Axonal Regeneration and Is Deficient in Experimental Diabetic Neuropathy

et al. 2008

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OBJECTIVE-Axonal regeneration is defective in both experimental and clinical diabetic neuropathy, contributing to loss of axonal extremities and neuronal dysfunction. The mechanisms behind this failure are not fully understood; however, a deficit in neurotrophic support and signaling has been implicated. RESEARCH DESIGN AND METHODS-We investigated the expression of neuritin (also known as candidate plasticity gene 15, cpg15) in the sensory nervous system of control rats and rats with streptozotocin (STZ)-induced diabetes using microarray PCR, Western blotting, and immunocytochemical analysis. The functional role of neuritin in sensory neurons in vitro was assessed using silencing RNA.RESULTS-Neuritin was expressed by a population of smalldiameter neurons in the dorsal root ganglia (DRG) and was anterogradely and retrogradely transported along the sciatic nerve in vivo. Nerve growth factor (NGF) treatment induced an increase in the transcription and translation of neuritin in sensory neurons in vitro. This increase was both time and dose dependent and occurred via mitogen-activated protein kinase or phosphatidylinositol-3 kinase activation. Inhibition of neuritin using silencing RNA abolished NGF-mediated neurite outgrowth, demonstrating the crucial role played by neuritin in mediating regeneration. Neuritin levels were reduced in both the DRG and sciatic nerve of rats with 12 weeks of STZ-induced diabetes, and these deficits were reversed in vivo by treatment with NGF.

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Impaired peripheral nerve regeneration in diabetes mellitus

Cited by 164 publications

References 130 publications

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Advanced Diabetic Neuropathy: A Point of no Return?

Neuritin Mediates Nerve Growth Factor–Induced Axonal Regeneration and Is Deficient in Experimental Diabetic Neuropathy

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