Neurofilaments and motor neuron disease

doi:10.1016/S0962-8924(97)01049-0

Trends in Cell Biology

Volume 7, Issue 6, June 1997, Pages 243-249

https://doi.org/10.1016/S0962-8924(97)01049-0 Get rights and content

Amyotrophic lateral sclerosis (ALS) is an adult-onset and heterogeneous neurological disorder that affects primarily motor neurons in the brain and spinal cord. Although multiple genetic and environmental factors might be implicated in ALS, the striking similarities in the clinical and pathological features of sporadic ALS and familial ALS suggest that similar mechanisms of disease may occur. A common and perhaps universal pathological finding in ALS is the presence of abnormal accumulations of neurofilaments (often called spheroids or Lewy body-like deposits) in the cell body and proximal axon of surviving motor neurons. Such neurofilament deposits have been widely viewed as a consequence of neuronal dysfunction, perhaps reflecting axonal transport defects. This review discusses the emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in a neurofilament gene associated with ALS, that neurofilament proteins can play a causative role in motor neuron disease.

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We have analyzed a mouse model of Charcot-Marie-Tooth disease 2E (CMT2E) harboring a heterozygous p.Asn98Ser (p.N98S) Nefl mutation, whose human counterpart results in a severe, early-onset neuropathy. Behavioral, electrophysiological, and pathological analyses were done on separate cohorts of Nefl ^N98S/+ mutant mice and their wild type Nefl ^+/+ littermates between 8 and 48 weeks of age. The motor performance of Nefl ^N98S/+ mice, as evidenced by altered balance and gait measures, was impaired at every age examined (from 6 to 25 weeks of age). At all times examined, myelinated axons were smaller and contained markedly fewer neurofilaments in Nefl ^N98S/+ mice, in all examined aspects of the PNS, from the nerve roots to the distal ends of the sciatic and caudal nerves. Similarly, the myelinated axons in the various tracts of the spinal cord and in the optic nerves were smaller and contained fewer neurofilaments in mutant mice. The myelinated axons in both the PNS and the CNS of mutant mice had relatively thicker myelin sheaths. The amplitude and the nerve conduction velocity of the caudal nerves were reduced in proportion with the diminished sizes of myelinated axons. Conspicuous aggregations of neurofilaments were only seen in primary sensory and motor neurons, and were largely confined to the cell bodies and proximal axons. There was evidence of axonal degeneration and regeneration of myelinated axons, mostly in distal nerves. In summary, the p.N98S mutation causes a profound reduction of neurofilaments in the myelinated axons of the PNS and CNS, resulting in substantially reduced axonal diameters, particularly of large myelinated axons, and distal axon loss in the PNS.
Gene Therapy for Amyotrophic Lateral Sclerosis: Therapeutic Transgenes
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Amyotrophic lateral sclerosis (ALS) is a disease with a poorly understood etiology. There are a wide variety of abnormalities present, including mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, astrogliosis and microgliosis, loss of innervation of neuromuscular junctions, and death of motor neurons. However, the relative contribution of these factors to disease initiation and progression is unclear at best, making it difficult to know which one or ones to focus on. Therefore, a wide variety of approaches have been investigated to treat this disorder, including gene therapy, cell therapy, and novel drugs. This chapter will focus on the therapeutic transgenes that have been studied to date. These transgenes range from those that address a single abnormality, such as apoptosis, to those that are expected to treat several defects simultaneously. While this range of approaches has demonstrated some improvement in the ALS phenotype in animal models, none has become the silver bullet that will halt ALS in its tracks.
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Citation Excerpt :
One of the main findings supporting axonal transport deficits contributing to neurodegeneration is the axonal and cell body accumulation of organelles and other proteins observed in human neurodegenerative diseases (De Vos et al., 2008). Regarding ALS, several works demonstrated the accumulation of neurofilaments in MN cell bodies in human patients, suggesting that axonal transport is impaired in these cells (Hirano et al., 1984; Julien, 1997; Julien et al., 1998; Schmidt et al., 1987). Additionally, abnormalities of organelle axonal trafficking have been described in ALS patients (Breuer et al., 1987).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motoneurons, leading to muscle weakness and paralysis, and finally death. Considerable recent advances have been made in basic research and preclinical therapeutic attempts using experimental models, leading to increasing clinical and translational research in the context of this disease. In this review we aim to summarize the most relevant findings from a variety of aspects about ALS, including evaluation methods, animal models, pathophysiology, and clinical findings, with particular emphasis in understanding the role of every contributing mechanism to the disease for elucidating the causes underlying degeneration of motoneurons and the development of new therapeutic strategies.
The complex molecular biology of Amyotrophic Lateral Sclerosis (ALS)
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Citation Excerpt :
Accumulation of neurofilaments, which maintain axonal diameter and structural integrity in motor neurons, is a long-recognized hallmark of ALS pathology in humans and mouse models and is thought to contribute to the selective vulnerability of long, large-caliber motor axons.2,48,226–228 Neurofilaments consist of light (NF-L), medium (NF-M), and heavy (NF-H) subunits, in equal proportion, and their proper assembly is crucial to the maintenance and extension of vulnerable large-caliber motor axons.229,230 Misassembly of neurofilaments due to over- or under-expression, mutation, or deficient transport of individual subunits results in their accumulation, further hindrance of axonal transport, and eventual motor neuron death.231–236
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that causes selective death of motor neurons followed by paralysis and death. A subset of ALS cases is caused by mutations in the gene for Cu, Zn superoxide dismutase (SOD1), which impart a toxic gain of function to this antioxidant enzyme. This neurotoxic property is widely believed to stem from an increased propensity to misfold and aggregate caused by decreased stability of the native homodimer or a tendency to lose stabilizing posttranslational modifications. Study of the molecular mechanisms of SOD1-related ALS has revealed a complex array of interconnected pathological processes, including glutamate excitotoxicity, dysregulation of neurotrophic factors and axon guidance proteins, axonal transport defects, mitochondrial dysfunction, deficient protein quality control, and aberrant RNA processing. Many of these pathologies are directly exacerbated by misfolded and aggregated SOD1 and/or cytosolic calcium overload, suggesting the primacy of these events in disease etiology and their potential as targets for therapeutic intervention.
ALS genetic modifiers that increase survival of SOD1 mice and are suitable for therapeutic development
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One extremity, the tail region, is comprised of lysine–serine–proline (KSP) motifs that can be phosphorylated and are important for regulating neurofilament assembly. An association of neurofilaments with neurodegeneration is represented by mutations in the neurofilament gene in ALS patients (Al-Chalabi et al., 1999; Figlewicz et al., 1994; Julien, 1997) and the identification of neurofilament accumulation in transgenic SOD1 mutant mice and patients affected by sporadic and familiar SOD1-related ALS (Rouleau et al., 1996). Also, over-expression of one or more NF subunits seems to induce ALS-like disease (Côté et al., 1993; Lee et al., 1994; Xu et al., 1993), probably through two pathogenic mechanisms: the formation of NF inclusions that interfere with axonal transport and inclusions that incorporate and inactivate functional cellular organelles (Tu et al., 1997).
Amyotrophic lateral sclerosis (ALS) is a frequently fatal motor neuron disease without any cure. To find molecular therapeutic targets, several studies crossed transgenic ALS murine models with animals transgenic for some ALS target genes. We aimed to revise the new discoveries and new works in this field. We selected the 10 most promising genes, according to their capability when down-regulated or up-regulated in ALS animal models, for increasing life span and mitigating disease progression: XBP-1, NogoA and NogoB, dynein, heavy and medium neurofilament, NOX1 and NOX2, MLC-mIGF-1, NSE-VEGF, and MMP-9. Interestingly, some crucial modifier genes have been described as being involved in common pathways, the most significant of which are inflammation and cytoskeletal activities. The endoplasmic reticulum also seems to play an important role in ALS pathogenesis, as it is involved in different selected gene pathways. In addition, these genes have evident links to each other, introducing the hypothesis of a single unknown, common pathway involving all of these identified genes and others to be discovered.
Axotomy-induced cytoskeleton changes in unmyelinated mammalian central nervous system axons
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Oligodendrocyte-derived myelin retards the ability of CNS axons to regenerate following transection. The intrinsic response of CNS axons to an axotomy insult may be vastly different in the absence of myelin. However, the paucity of adequate experimental models has limited detailed investigation of cellular behaviour following axon transection in an unmyelinated CNS environment. In this study we perform laser-induced axotomy of the porcine retinal ganglion cell axon, a physiologically unmyelinated, mature CNS axon that is structurally similar to humans to infer knowledge about axonal behaviour in the absence of myelin. Axotomy-induced changes to the neuronal cytoskeleton and supporting astrocytes during the early stages after transection are delineated by examining the sequence of neurofilament subunit, microtubule (TUB), microtubule associated protein (MAP), glial fibrillary acidic protein (GFAP) and terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) modification. Axonal transection induced an increase in the expression of neurofilament light at regions within, and immediately adjacent to, sites of axotomy. Other neurofilament subunits were not altered at sites of transection. Unlike myelinated axons where an increase in GFAP staining within hypertrophic glial scars have been shown to inhibit axonal repair we demonstrate a decrease in GFAP staining within regions of increased or preserved neurofilament expression. The behaviour of TUB and MAP proteins following transection of unmyelinated CNS axons are similar to what has previously been described in myelinated CNS axons. This study provides fundamental insights into astrocyte and axonal behaviour acutely after axotomy and demonstrates a series of degenerative events in unmyelinated CNS axons, which in comparison to prior reports are different to myelinated CNS axons. The findings of this report have relevance to understanding pathogenic mechanisms underlying neuro-degeneration in the CNS.

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Trends in Cell Biology

ReviewNeurofilaments and motor neuron disease

Neuron

J. Mol. Biol.

J. Biol. Chem.

Gene

Cell

Cell

Cell

Neuron

Neuroscience

J. Biol. Chem.

Mol. Brain Res.

Neurobiol. Aging

Cell

J. Biol. Chem.

Cell

Neuron

J. Chem. Neuroanat.

J. Neurol. Sci.

J. Cell Biol.

Lab. Invest.

J. Cell Biol.

J. Cell Biol.

Annu. Rev. Biochem.

EMBO J.

J. Neurosci.

Review
Neurofilaments and motor neuron disease