Toxic neurofilamentous axonopathies– accumulation of neurofilaments and axonal degeneration

Abstract

A number of neurotoxic chemicals induce accumulation of neurofilaments in axonal swellings that appear at varying distances from the cell body. This pathology is associated with axonal degeneration of different degrees. The clinical manifestation is most commonly that of a mixed motor-sensory peripheral axonopathy with a distoproximal pattern of progression, as in cases of chronic exposure to n-hexane and carbon disulphide. It has been demonstrated that protein adduct formation is a primary molecular mechanism of toxicity in these axonopathies, but how this mechanism leads to neurofilament accumulation and axonal degeneration remains unclear. Furthermore, little is known regarding the mechanisms of neurofilamentous axonopathy caused by 3,3′-iminodipropionitrile, an experimental toxin that induces proximal axon swelling that is strikingly similar to that found in early amyotrophic lateral sclerosis. Here, we review the available data and main hypotheses regarding the toxic axonopathies and compare them with the current knowledge of the biological basis of neurofilament transport. We also review recent studies addressing the question of how these axonopathies may cause axonal degeneration. Understanding the mechanisms underlying the toxic axonopathies may provide insight into the relationship between neurofilament behaviour and axonal degeneration, hopefully enabling the identification of new targets for therapeutic intervention. Because neurofilament abnormalities are a common feature of many neurodegenerative diseases, advances in this area may have a wider impact beyond toxicological significance.

A Stochastic Multiscale Model That Explains the Segregation of Axonal Microtubules and Neurofilaments in Neurological Diseases

“…It is important to note that the impairment of neurofilament transport that leads to microtubule-neurofilament segregation in toxic neuropathies and neurodegenerative diseases also leads eventually to focal neurofilament accumulations and axonal swellings (see Introduction). Since microtubules are the tracks along which neurofilaments move, and since microtubule-neurofilament segregation appears early and precedes neurofilament accumulation and axonal swelling, it has been hypothesized that the segregation reflects the uncoupling of neurofilaments from their transport machinery [24,28]. Our modeling supports this hypothesis, but the molecular mechanism is unclear.…”

“…Neurofilaments has been observed to accumulate abnormally in axons in many neurodegenerative diseases including amyotrophic lateral sclerosis, hereditary spastic paraplegia, giant axonal neuropathy and Charcot-Marie-Tooth disease (also known as hereditary distal motor and sensory neuropathy) [5,[19][20][21][22][23], and also in many toxic neuropathies [24][25][26][27][28]. In extreme cases, these accumulations can lead to giant balloon-like axonal swellings [29][30][31][32][33][34].…”

“…IDPN is a compound closely related to the naturally occurring food poison 3-aminopropionitrile which causes the neurological disorder lathyrism [65][66][67][68], and 2,5-hexanedione is a metabolite of the industrial solvent hexane. The mechanism of toxicity is not known, but it is thought to involve chemical modification of neurofilaments, which presumably disrupts their normal interactions with microtubules in some way [25,28,[69][70][71][72][73][74]. Systemic administration of IDPN or 2,5-hexanedione to rats causes selective impairment of neurofilament transport [75][76][77][78][79], focal accumulations of axonal neurofilaments leading to axon enlargement, and neurological defects similar to amyotrophic lateral sclerosis (ALS) in humans [80][81][82][83].…”

Neurofilaments and Neurofilament Proteins in Health and Disease

“…Exposure to a variety of chemical agents, such as β,β’-iminodipropionitrile (IDPN), aluminum, lead, acrylamide, arsenic, carbon disulfide, and 2,5-hexanedione, can chemically modify NF subunits, leading to neurodegeneration characterized by accumulation of phosphorylated NFs (Llorens 2013). IDPN induces abnormal cross-linking of hyper-phosphorylated NFs, probably mediated through the NF-H subunit (Zhu et al 1998), resulting in NF aggregation and subsequent segregation from MTs (Eyer et al 1989).…”

Intermediate filament accumulation can stabilize microtubules inCaenorhabditis elegansmotor neurons

“…Since we found that loss of IFs in tba-1(gf) dlk-1(0) animals could restore MT dynamics and promote synapse rewiring, we next wanted to test if pharmacologically manipulating IF assembly would result in a similar phenotype. 2,5-Hexanedione (2,5-HD) is a metabolite of the industrial solvent hexane that causes IF disruption upon application to cultured mammalian cells and alters NF interaction with MTs in mammalian axons, although the precise mechanism of 2,5-HD action is unclear (33)(34)(35). We first characterized the effects of 2,5-HD exposure on C. elegans IF assembly using IFP-1::GFP.…”