Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral neuropathy is a particularly debilitating complication of both type 1 and type 2 diabetes characterized by sensory and motor neuron damage and decreased circulating levels of insulin-like growth factor 1 (IGF-1). Quite often, an early hyperalgesia is followed by hypoalgesia and muscle weakness. Hypoalgesia can lead to significant morbidity for which there is no current treatment. Hyperglycemic, streptozotocin (STZ)-induced rodent models reproduce these symptoms. We investigated whether increasing systemic IGF-1 could improve neuronal function in hyper- and hypoalgesic STZ-treated mice. Increased circulating levels of IGF-1 were achieved by delivering a plasmid or adeno-associated viral (AAV) vector bearing mouse IGF-1 to the liver. Treating mice in the hyperalgesia stage prevented later hypoalgesia. Treating mice in the hypoalgesia stage reversed existing hypoalgesia. This latter effect could be seen by merely restoring IGF-1 serum levels to normalcy, which was possible to achieve by IGF-1 gene therapy or insulin treatment. Sensory nerve functional correction was seen to be correlated with attenuated Schwann cell vacuolization and demyelination in peripheral sensory nerve fibers. A further increase in serum IGF-1 levels with gene therapy also improved motor function, consistent with the observed prevention of both muscle atrophy and peripheral motor nerve fiber demyelination. These results suggest that the restoration of systemic levels of IGF-1 may prove to be a highly effective therapeutic modality for treating diabetic peripheral neuropathy.
Mol Ther 2008 Aug
PMID:Systemic Insulin-like growth factor-1 reverses hypoalgesia and improves mobility in a mouse model of diabetic peripheral neuropathy. 1854 23

Abnormal wound healing is a major complication of both type 1 and type 2 diabetes, with nonhealing foot ulcerations leading in the worst cases to lower-limb amputation. Wound healing requires the integration of complex cellular and molecular events in successive phases of inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialisation. A link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30-50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. Indeed, a bidirectional connection between the nervous and the immune systems and its role in wound repair has emerged as one of the focal features of the wound-healing dogma. This review provides a broad overview of the mediators of this connection, which include neuropeptides and cytokines released from nerve fibres, immune cells and cutaneous cells. In-depth understanding of the signalling pathways in the neuroimmune axis in diabetic wound healing is vital to the development of successful wound-healing therapies.
Expert Rev Mol Med 2009 Jan 13
PMID:Inflammation and neuropeptides: the connection in diabetic wound healing. 1913 53

Cisplatin, carboplatin, and oxaliplatin anticancer drugs are commonly used to treat lung, colorectal, ovarian, breast, head and neck, and genitourinary cancers. However, the efficacy of platinum-based drugs is often compromised because of the substantial risk for severe toxicities, including neurotoxicity. Neurotoxicity can result in both acute and chronic debilitation. Moreover, colorectal cancer patients treated with oxaliplatin discontinue therapy more often because of peripheral neuropathy than tumor progression, potentially compromising patient benefit. Numerous methods to prevent neurotoxicity have thus far proven unsuccessful. To circumvent this life-altering side effect while taking advantage of the antitumor activities of the platinum agents, efforts to identify mechanism-based biomarkers are under way. In this review, we detail findings from the current literature for genetic markers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy. These data have the potential for broad clinical implications if mechanistic associations lead to the development of toxicity modulators to minimize the noxious sequelae of platinum chemotherapy.
Mol Cancer Ther 2009 Jan
PMID:Platinum neurotoxicity pharmacogenetics. 1913 8

Porphyrin precursors and porphyrins were measured in three patients with recurrent attacks of acute intermittent porphyria and end-stage renal disease (ESRD): two patients on hemodialysis and one on peritoneal dialysis. Plasma porphobilinogen (PBG) and porphyrins were considerably increased in the three patients. In a previous study, the mean urinary and plasma PBG/ALA ratio in biochemically active AIP patients with conserved renal function was 2.0 (normal 0.3) and plasma porphyrin levels were normal (< 10 nmol/L). In this study we show that the progression to ESRD was paralleled by an increase in urinary and plasma PBG/ALA ratio reaching levels above 6 and higher. Plasma porphyrin increased to levels above 1000 nmol/L causing cutaneous lesions resembling porphyria cutanea tarda. The porphyrin precursors were readily filtered by dialysis membranes but not the porphyrins. The development of kidney failure was a devastating complication in these AIP patients with chronic active disease, leading to unavoidable deterioration of peripheral veins, progression of peripheral neuropathy, dialysis treatment and secondary cutaneous lesions. The clinical course could not be reversed by medical treatment in any of the cases. Today, combined liver and kidney transplantation should be considered as a therapeutic option.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Porphyrin precursors and porphyrins in three patients with acute intermittent porphyria and end-stage renal disease under different therapy regimes. 1926 4

Acute intermittent porphyria (AIP) is an inherited metabolic disease due to a deficiency of the hydroxymethylbilane synthase in the haem biosynthesis. It manifests with occasional neurovisceral crises due to overproduction of porphyrin precursors such as aminolaevulinic acid (ALA) which is released from the liver to the circulation. The majority of the acute attacks manifest as a combination of abdominal pain, mild mental symptoms and autonomic dysfunction mainly due to vagal insufficiency. However, both acute peripheral neuropathy and encephalopathy may develop if an acute attack proceeds especially due to administration of porphyrinogenic drugs. Acute porphyric neuropathy is predominantly motor and associates with a history of abdominal pain and dysautonomia, CNS involvement and mild hepatopathy. Other features include preservation of achilles reflexes while global hyporeflexia and neuropathic or myalgic pain. The pathogenesis of porphyric neuropathy is complex but overproduction of ALA via direct neurotoxicity, oxidative damage, and modification of glutamatergic release may initiate the neuronal damage. Acute encephalopathy manifests as a combination of mental symptoms, seizures, SIADH, but rarely focal CNS deficits. Posterior reversible encephalopathy syndrome (PRES), which has been found in patients' MRI during an acute attack with severe encephalopathy, could explain the pathogenesis of encephalopathy and seizures in AIP. Neurological manifestations are unspecific and careful interpretation of abnormal excretion of porphyrin precursors should be done before the symptoms can be related to inherited acute porphyrias and not to secondary porphyrinuria. Currently the prognosis of neuropathy and encephalopathy in AIP is good even in severe attacks, but physicians should be aware of a potentially fatal outcome of the disease.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Neurological manifestations of acute intermittent porphyria. 1926 5

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal beta-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months, respectively. Eleven patients with infantile (n = 6) and juvenile (n = 5) GM2g received oral miglustat at 30-200 mg t.i.d. adjusted to the body surface area. Patients underwent pharmacokinetic assessments on day 1 and at month 3. The pharmacokinetics of miglustat were described by a 2-compartmental model with a lag time, median time to maximum concentration of 2.5 h, and terminal half-life of about 10 h. The pharmacokinetics were time-independent, and did not differ between infantile and juvenile cohorts. The accumulation index was 1.7. Among infantile GM2g patients, the major drug-related adverse events (DRAEs) were abdominal discomfort and flatulence. In the juvenile group, however, the major DRAEs observed were diarrhea and weight loss. One juvenile patient developed peripheral neuropathy, and others showed progression of already established neuropathy, which was judged to be part of the natural progression of the disease. Some mild laboratory abnormalities observed were either transient or attributable to concomitant medications. Miglustat showed similar pharmacokinetic parameters in all patients, with no specific difference between infantile and juvenile forms. Miglustat was shown to be a safe drug, with mild to moderate diarrhea, as an age-dependent DRAE, which was controlled by dietary modification.
Mol Genet Metab 2009 Aug
PMID:Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. 1944 53

The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies reveal tissue-specific effects of these Cx31 disease-associated mutations. The Cx31 mutants (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 are associated with EKV and the mutant (66delD)Cx31 with peripheral neuropathy and hearing loss, however the mechanisms of pathogenesis remain to be elucidated. Expression of (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 in vitro, but not (WT)Cx31 or (66delD)Cx31, cause elevated levels of cell-type specific cell death. Previous studies suggest that Cx-associated cell death may be related to abnormal 'leaky' hemichannels but we produced direct evidence against that being the major mechanism. Additionally, our immunocytochemistry showed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not (WT)Cx31 or (66delD)Cx31. We conclude that the endoplasmic reticulum (ER) stress leading to the UPR is the main mechanism of mutant Cx31-associated cell death. These results indicate that, in vivo, ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin.
Hum Mol Genet 2009 Dec 15
PMID:EKV mutant connexin 31 associated cell death is mediated by ER stress. 1975 82

Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases--including Parkinson's, Alzheimer's and Huntington's disease--involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy.
Hum Mol Genet 2009 Oct 15
PMID:Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. 1980 93

Axonal excitability testing can provide new insights into the ionic mechanisms underlying the pathophysiology of hyperexcitability of motor and sensory axons in human neuropathies. Threshold tracking was developed in the 1990's to non-invasively measure a number of axonal excitability indices that depend on sodium and potassium channel function, and this makes it possible to monitor the effects of pharmacologic intervention with ion channel modulators. This paper reviews recent advances in ionic-pathophysiological studies in humans. (1) Neuropathic pain or muscle cramp/fasciculation is partly caused by hyperexcitability of the injured axons. The enhanced excitability can result from altered ion channel function; such as an increase in persistent sodium currents. Persistent sodium currents can be reliably estimated using threshold tracking. In peripheral neuropathy, persistent sodium currents usually increase possibly due to over-expression of sodium channels associated with axonal regeneration, and could be responsible for ectopic firings. Administration of sodium channel blockers such as mexiletine, results in marked alleviation of muscle cramping in parallel with a decrease in nodal persistent sodium currents. (2) In diabetic neuropathy, the activation of the polyol pathway mediated by an enzyme, aldose reductase, leads to reduced Na(+)/K(+) pump activity, and intra-axonal sodium accumulation; sodium currents are reduced presumably due to decreased trans-axonal sodium gradient. Aldose reductase inhibitiors improve nodal sodium currents, as well as nerve conduction, and this can be objectively assessed by threshold tracking. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms by monitoring the corresponding ionic currents. is of clinical relevance, because once a specific ionic conductance is identified, pharmacologic blocking or modulation could provide a new therapeutic option.
Curr Mol Pharmacol 2008 Jan
PMID:Pharmacologic intervention in axonal excitability: in vivo assessment of nodal persistent sodium currents in human neuropathies. 2002 24

Mutations in the functionally uncharacterized protein SH3TC2 are associated with the severe hereditary peripheral neuropathy, Charcot-Marie-Tooth disease type 4C (CMT4C). Similarly, to other proteins mutated in CMT, a role for SH3TC2 in endocytic membrane traffic has been previously proposed. However, recent descriptions of the intracellular localization of SH3TC2 are conflicting. Furthermore, no clear functional pathogenic mechanisms have so far been proposed to explain why both nonsense and missense mutations in SH3TC2 lead to similar clinical phenotypes. Here, we describe our intracellular localization studies, supported by biochemical and functional data, using wild-type and mutant SH3TC2. We show that wild-type SH3TC2 targets to the intracellular recycling endosome by associating with the small GTPase, Rab11, which is known to regulate the recycling of internalized membrane and receptors back to the plasma membrane. Furthermore, we demonstrate that SH3TC2 interacts preferentially with the GTP-bound form of Rab11, identifying SH3TC2 as a novel Rab11 effector. Of clinical pathological relevance, all SH3TC2 constructs harbouring disease-causing mutations are shown to be unable to associate with Rab11 with consequent loss of recycling endosome localization. Moreover, we show that wild-type SH3TC2, but not mutant SH3TC2, influences transferrin receptor dynamics, consistent with a functional role on the endocytic recycling pathway. Our data therefore implicate mistargeting of SH3TC2 away from the recycling endosome as the fundamental molecular defect that leads to CMT4C.
Hum Mol Genet 2010 Mar 15
PMID:Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C. 2002 92


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