Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies?

Spencer, Peter S.; Sabri, Mohammad I.; Schaumburg, Herbert H.; Moore, Charlotte E.

doi:10.1002/ana.410050602

Cited by 217 publications

(60 citation statements)

References 27 publications

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“…NF-containing distal axonal enlargements. Spencer et al (14) have suggested that six-carbon compounds and their derivatives impair enzymes of intermediary metabolism, causing a progressive failure of the energy supply needed for NF transport; hence, NF would stop and accumulate focally. According to Graham et al (28) 2,5-HxD reacts directly with 6-amino groups of lysine residues of NF proteins to form aromatic pyrrole derivatives; autooxidation of these pyrroles would lead to cross-link formation; the high stability and low turnover rate of axonal NF would make them especially vulnerable to this toxic effect; aggregates of NF, progressively cross-linked during their migration along the axon, would be transported at decreasing rates and eventually blocked at distal nodes of Ranvier.…”

Section: A3mentioning

confidence: 99%

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Giant axonal neuropathy: acceleration of neurofilament transport in optic axons.

Monaco¹,

Autilio-Gambetti²,

Zabel³

et al. 1985

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

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Giant axonal neuropathies are a group of acquired and inherited human diseases morphologically characterized by accumulation of neurofilaments (NF) in enlargements of preterminal regions of central and peripheral axons. Slow axonal transport was studied in the optic systems of rats treated with 2,5-hexanedione, a toxic compound that produces an experimental model of giant axonal neuropathy. The transport rate of NF and of two other polypeptides of Mr 64,000 and 62,000 were selectively increased. Other components of the slow axonal transport were not affected. Acceleration of labeled NF was also observed when 2,5-hexanedione was given after [35S~methionine administration. Morphometric analysis revealed that the number of NF and the axon size were decreased in regions of optic axons proximal to the enlargements. It is suggested that acceleration of NF transport leads to a longitudinal redistribution of NF: NF decrease proximally and increase distally, forming NF-containing enlargements. Evidence was obtained that polypeptides of Mr 64,000 and 62,000 are cytoskeletal components related to intermediate filaments, normally migrating with the component a of the slow axonal transport. The 2,5-hexanedione axon may provide insight into the pathogenesis of inherited and acquired giant axonal neuropathies and offers a model to investigate the relationship between number of NF and axonal size in central axons.Axonal transport involves the migration of highly ordered complexes of proteins at five distinct rates (1). In mammalian optic axons two groups of proteins, slow component a (SCa) and slow component b (SCb), have transport rates of 0.3 mm/day and 2-3 mm/day, respectively (2). SCa comprises neurofilaments (NF), tubulin, and microtubule-associated proteins, whereas SCb carries over 200 polypeptides, including actin, calmodulin, neuronal-specific enolase, and creatine kinase (3).The use of experimental models has added new insight to the role that disturbances of the axonal transport play in the pathophysiology of human diseases of the central and peripheral nervous systems.Giant axonal neuropathies are a group of diseases comprising toxic as well as inherited conditions (4, 5). The pathological hallmark of these diseases is the presence of masses of NF producing focal enlargements in the preterminal regions of axons. In advanced stages of the neuropathy, the enlargements extend proximally and the distal part of the involved axons eventually undergoes degeneration in several central and peripheral axonal pathways. However, in experimental models no degeneration has been observed in the primary optic pathway despite the presence of numerous enlarged axons (6-8).Methyl n-butyl ketone, n-hexane, and their metabolite 2,5-hexanedione (2,5-HxD) (9, 10) are toxic agents that cause distal giant axonopathies. Methyl n-butyl ketone and n-hexane are widely used as solvents and have caused outbreaks of polyneuropathies among industrial workers (11, 12) and in individuals intentionally inhaling glue vapors (13). The distal gi...

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Section: A3mentioning

confidence: 99%

“…Two main hypotheses have been put forward, both assuming that NF are transported at decreasing rates and are eventually blocked (14,15). However, slow axonal transport has not been studied.…”

mentioning

confidence: 99%

Giant axonal neuropathy: acceleration of neurofilament transport in optic axons.

Monaco¹,

Autilio-Gambetti²,

Zabel³

et al. 1985

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

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“…Investigations on the axonal flow of labeled protein in hexacarbon neuropathy show that slow axonal transport is impaired with a secondary focal slowing of fast axonal transport (82). In acrylamide intoxication the slow transport components appear not to be affected, while there are local disturbances of the fast transport in distal parts of the axon.…”

Section: Axonal Transport and Distal Axonopathymentioning

confidence: 99%

“…Selected list of industrial toxic chemicals producing structural damage in the peripheral nervous system (32,45,83,84,86). 82). However it is not known whether the delay of axonal transport is the primary defect, as it develops at the same time as the appearance of the morphologicallesions in hexacarbon-induced neuropathy (44).…”

Section: Advances In the Understanding Of The Pathogenesis Cellular Tmentioning

confidence: 99%

Occupational toxic neuropathies--an update.

He¹

1985

Scand J Work Environ Health

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Occupational toxic neuropathies--an update.by He F This article in PubMed: www.ncbi.nlm.nih.gov/pubmed/2999969 REVIEWS Scand j work environ health II (1985) [321][322][323][324][325][326][327][328][329][330] Occupational toxic neuropathies -An update by Fengsheng He, MD1 HE F. Occupational toxic neuropathies -An update. Scand J Work Environ Health II (1985) 321-330. Peripheral neuropathy is the commonest neurol ogical syndrome produced by indu strial and agricultural chemicals. A number of chemicals have been recently found to be neurotoxins; in addition some known occupational neurotoxic hazards more often produ ce subtle alterat ions in the peripher al nervous system. Ther e have been problem s of both evaluating neuroto xic effects and identifying toxic causes. This article reviews and discusses th e current research and progress covering neurophysiological, neuropathological, biochemical , and epidemiologic approaches in clinical and experimental neurotoxicology, as related to the assessment and path ogenesis of occupa tion al toxic neuropathies.Key terms: assessment , clinical neur ophysiological testing, distal axonopathy, epidemiologic investigation, identi fication, neuropathological approach, pathogenesis, toxic causes.Alon g with the development of various chemical industries there has been a growing list of indu strial chemicals which can cause damage to the peripheral nervous system . On the other hand, occupational exposure to low levels of known neurotoxins more oft en causes subtle alterations of peripheral nervous function. This occurrence raises problems in occupational health practice and stimulates research concerning the early diagnosi s and prevention of occupational toxic neuropathies. In the meantime , modern technique s of neurophysiology, neuropathology, and biochemistry have been introduced and utilized to explore the mechani sms of some neurotoxic effects . All these methods lead to a substantial amount of progress in evaluat ing and understanding occupational toxic neuropathies, which have been reviewed in this article. PROGRESS IN ASSESSMENT AND IDENTIFICATIONThe diagnosis of chemically-induced neuropathies can be reasonably made in those subj ects who have a verified history of exposure to neurotoxins and characteristic clinical evidence of neuropathy with exclusion of other causative factors. But there are some asymptomatic individuals under neurotoxicologic risk who may be suspected of having subclinical peripheral neuropathies and, on the other hand, a number of symptomatic patients having the presumptive diagnosis of polyneuropathy without a known etiology. In these cases, the question of either the existence or the etiology of the peripheral neuropathies remain s to be settled. Detection of neurotoxic effects on the peripheral nervous system

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“…Some have postulated that neurofilaments accumulate because of a defect in axonal transport, perhaps secondary to a defect in energy metabolism (14). Cavanagh and Bennetts have suggested that the defect may lie in the catabolism of neurofilaments (15).…”

Section: Introductionmentioning

confidence: 99%

In vitro evidence that covalent crosslinking of neurofilaments occurs in gamma-diketone neuropathy.

Graham¹,

Szakál-Quin²,

Priest³

et al. 1984

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

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We have postulated that the toxic neuropathies associated with neurofilament-filled axonal swellings have a common pathogenesis, the covalent crosslinking of neurofilaments during anterograde transport. The newly described -diketone, 3,4-dimethyl-2,5-hexanedione (DMHD), is a more potent analogue of the toxic metabolite of n-hexane, 2,5-hexanedione. The axonal swellings observed in DMHD toxicity are in the proximal axon, as seel Ah iutoxication with ,4l'-iminodipropionitrile, rather tha. ln the distal axon, where neurofilamentous swellings are observed in n-hexane, carbon disulfide, and acrylamide neurotoxicity. In these studies, 14C-labeled DMHD and 2-butanone were synthesized and allowed to react with peripheral nerve. Only 14C-labeled DMHD resulted in stable radiolabeled protein polymers, which were retained by nitrocellulose filters with pore sizes as large as 12 ,um. More specific evidence for covalent crosslinking of neurofilaments was obtained when DMHD was allowed to react with peripheral nerve in which the neurofilaments had been pulse-labeled with L-[35S]methionine.The common solvent, n-hexane, has resulted in sensorimotor neuropathies in industry (1) and after inhalation for its euphoric effects (2). In humans, as well as in experimental animals, the initial alteration is an accumulation of 10-nm neurofilaments in the distal, preterminal axon (3). This is accompanied by huge swellings of the axon, most often proximal to nodes of Ranvier (4). Marked distortions of nodal and paranodal structure are associated with the masses of neurofilaments (5, 6). In large myelinated axons, the neurofilament-filled axonal swellings are followed by Wallerian-like degeneration of the distal axon (4). A similar sequence of events is observed after exposure to carbbn disulfide (7) or acrylamide (8), although with the latter toxicant neurofilament-filled axonal swellings are a less common event. An inherited neuropathy in children, giant axonal neuropathy, is also characterized by neurofilamentous swellings of the distal axon (9). p,B,p-Iminodipropionitrile is a compound that has produced a unique clinical and pathological picture in which the neurofilament-filled axonal swellings occur in the proximal rather than the distal axon (10-12). This proximal axonopathy has been classified separately from the distal axonopathies caused by n-hexane, carbon disulfide, or acrylamide. Similar proximal swellings filled with neurofilaments are seen early in amyotrophic lateral sclerosis (13).The genesis of the neurofilament accumulations in these disorders has been a point of great controversy. Some have postulated that neurofilaments accumulate because of a defect in axonal transport, perhaps secondary to a defect in energy metabolism (14). Cavanagh and Bennetts have suggested that the defect may lie in the catabolism of neurofilaments (15). Studies in this laboratory have led to the proposThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertise...

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Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies?

Cited by 217 publications

References 27 publications

Giant axonal neuropathy: acceleration of neurofilament transport in optic axons.

Giant axonal neuropathy: acceleration of neurofilament transport in optic axons.

Occupational toxic neuropathies--an update.

In vitro evidence that covalent crosslinking of neurofilaments occurs in gamma-diketone neuropathy.

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