Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis

Collard, Jean-François; Côté, Francine; Julien, Jean‐Pierre

doi:10.1038/375061a0

Cited by 442 publications

(265 citation statements)

References 12 publications

Supporting

Mentioning

251

Contrasting

Unclassified

Order By: Relevance

“…Hence, axonal transport of organelles might not be a suitable target to therapeutically prevent the irreversible loss of neurons or axons in ALS, although in other neurodegenerative diseases, this might clearly be a promising strategy (34). However, our study does not exclude disturbances in slow axonal transport (35,36) or changes in cargo composition (27) as important steps in ALS pathogenesis, and does not contradict the view that organelle transport deficits can accelerate axon degeneration, e.g., in the SOD G93A model (25). Moreover, our argument strictly applies only to mitochondria and endosome-derived vesicles.…”

Section: Discussionmentioning

confidence: 51%

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Marinković

Reuter

Brill

et al. 2012

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

View full text Add to dashboard Cite

Axonal transport deficits have been reported in many neurodegenerative conditions and are widely assumed to be an immediate causative step of axon and synapse loss. By imaging changes in axonal morphology and organelle transport over time in several animal models of amyotrophic lateral sclerosis (ALS), we now find that deficits in axonal transport of organelles (mitochondria, endosomes) and axon degeneration can evolve independently. This conclusion rests on the following results: (i) Axons can survive despite long-lasting transport deficits: In the SOD G93A model of ALS, transport deficits are detected soon after birth, months before the onset of axon degeneration. (ii) Transport deficits are not necessary for axon degeneration: In the SOD G85R model of ALS, motor axons degenerate, but transport is unaffected. (iii) Axon transport deficits are not sufficient to cause immediate degeneration: In mice that overexpress wild-type superoxide dismutase-1 (SOD WT ), axons show chronic transport deficits, but survive. These data suggest that disturbances of organelle transport are not a necessary step in the emergence of motor neuron degeneration.

show abstract

Section: Discussionmentioning

confidence: 51%

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Marinković

Reuter

Brill

et al. 2012

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

View full text Add to dashboard Cite

show abstract

“…Axonal damage was evident as formation of argyrophilic spheroids with intense immunolabeling for p-NF, n-NF, and b-APP as described earlier (Gentleman et al 1993;Collard et al 1995;Coleman 2005). The intense accumulation of p-NF in dt-MP mice indicates a disturbance of the axonal cytoskeleton, especially in the complex process of phosphorylation and dephosphorylation of neurofilaments (Meller et al 1994;King et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

et al. 2016

View full text Add to dashboard Cite

Dystonia musculorum is a neurodegenerative disorder caused by a mutation in the dystonin gene. It has been described in mice and humans where it is called hereditary sensory autonomic neuropathy. Mutated mice show severe movement disorders and die at the age of 3-4 weeks. This study describes the discovery and molecular, clinical, as well as pathological characterization of a new spontaneously occurring mutation in the dystonin gene in C57BL/6N mice. The mutation represents a 40-kb intragenic deletion allele of the dystonin gene on chromosome 1 with exactly defined deletion borders. It was demonstrated by Western blot, mass spectrometry, and immunohistology that mice with a homozygous mutation were entirely devoid of the dystonin protein. Pathomorphological lesions were restricted to the brain stem and spinal cord and consisted of swollen, argyrophilic axons and dilated myelin sheaths in the white matter and, less frequently, total chromatolysis of neurons in the gray matter. Axonal damage was detected by amyloid precursor protein and nonphosphorylated neurofilament immunohistology. Axonopathy in the central nervous system (CNS) represents the hallmark of this disease. Mice with the dystonin mutation also showed suppurative inflammation in the respiratory tract, presumably due to brain stem lesion-associated food aspiration, whereas skeletal muscles showed no pathomorphological changes. This study describes a novel mutation in the dystonin gene in mice leading to axonopathy in the CNS. In further studies, this model may provide new insights into the pathogenesis of neurodegenerative diseases and may elucidate the complex interactions of dystonin with various other cellular proteins especially in the CNS. KEYWORDS axonopathy; dystonia musculorum; dystonin deficiency; genomic deletion; spontaneous mutation A spontaneously occurring mutant was described in the mouse, in which the gene dystonin was affected (Ledoux 2011). Dystonin (Dst) [human gene name, DST; former name, bullous pemphigoid antigen 1 (BPAG1)] is a large cytoskeletal linker protein and crucial for maintaining cellular structural integrity (Young and Kothary 2008). Recent research in this field concentrates on the role of dystonin in central nervous tissue and neurological diseases, but not, however, on its parallel expression in musculature and skin.Mice with a mutated dystonin gene develop a severe sensory neuropathy called dystonia musculorum (Duchen 1976). Characteristics are a progressive loss of coordination of the limbs (ataxia) and an early death (Kothary et al. 1988;Guo et al. 1995). There are only few reports about patients with mutations of the human dystonin gene (Giorda et al. 2004;Groves et al. 2010;Edvardson et al. 2012).Several dystonin isoforms are generated from one genomic locus of 400 kb. They are expressed in the central nervous system (CNS) (predominant neuronal isoform "a," 617 kDa and "n," 344 kDa), muscles (predominant muscle isoform "b," 834 kDa), and skin (predominant skin isoform "e," 302 kDa) ( Figure 1 Pool et al...

show abstract

“…Axonal swellings are induced by neurotoxic chemicals (39), genetic ablation or expression of mutated genes in transgenic mice (32,40), and neurodegenerative diseases such as amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Wallerian degeneration, Alzheimer's disease and cerebrospinal ataxia (41)(42)(43)(44). In all these situations, the development of swellings has been proposed to be a late sign of impairments in axonal transport.…”

Section: Discussionmentioning

confidence: 99%

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

Garcia-Fresco

Sousa

Pillai

et al. 2006

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

121

View full text Add to dashboard Cite

Axo-glial junctions (AGJs) play a critical role in the organization and maintenance of molecular domains in myelinated axons. Neurexin IV͞Caspr1͞paranodin (NCP1) is an important player in the formation of AGJs because it recruits a paranodal complex implicated in the tethering of glial proteins to the axonal membrane and cytoskeleton. Mice deficient in either the axonal protein NCP1 or the glial ceramide galactosyltransferase (CGT) display disruptions in AGJs and severe ataxia. In this article, we correlate these two phenotypes and show that both NCP1 and CGT mutants develop large swellings accompanied by cytoskeletal disorganization and degeneration in the axons of cerebellar Purkinje neurons. We also show that ␣II spectrin is part of the paranodal complex and that, although not properly targeted, this complex is still formed in CGT mutants. Together, these findings establish a physiologically relevant link between AGJs and axonal cytoskeleton and raise the possibility that some neurodegenerative disorders arise from disruption of the AGJs.myelin ͉ paranodes ͉ cerebellum ͉ ataxia T he anatomical organization of myelinated fibers into distinct domains is the basis for the saltatory mode of action potential propagation. In the axons, these molecular domains (internode, juxtaparanode, paranode, and node of Ranvier) form as a result of specific polarization driven by signaling between the myelinating glial cells and neurons that has yet to be fully understood. In the paranodal region, closely apposed axon-glial membranes form specialized cell junctions, which resemble the ladder-like invertebrate septate junctions, and are referred to as paranodal septate junctions or paranodal axo-glial junctions (AGJs) (1-4).Three major proteins have been shown to localize to the paranodal AGJs: NCP1 (also known as Caspr1 or paranodin) and contactin (CNTN) on the axonal side and neurofascin (NF155), the 155-kDa isoform on the glial side (5-9). Although NF155 is the only known glial protein at the paranodal membrane, a number of nonparanodal glial proteins are required for proper formation, maintenance, and distribution of AGJs, as in the case of ceramide galactosyltransferase (CGT), proteolipid protein, myelin-basic protein, myelin-associated glycoprotein, 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase, and the transcription factor Nkx6-2 (10-17).Genetic ablation of NCP1 and CNTN in mice results in the loss of AGJs and a failure to segregate Na ϩ and K ϩ channels at the nodes and juxtaparanodes, respectively (5, 6). Similar phenotypes were observed at the paranodes in CGT mutants (18,19). CGT encodes an enzyme that is needed for the biosynthesis of two important myelin lipids, galactocerebroside and sulfatide (10,(18)(19)(20)(21). Using subcellular fractionation of NF155 in detergents, Rasband and coworkers (22) proposed a model in which myelin lipids assemble in stable lipid rafts to stabilize the clustering of NF155 at the glial side of AGJs. This model is consistent with the phenotype of CGT mutants in which defective biosynthes...

show abstract

Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis

Cited by 442 publications

References 12 publications

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

Contact Info

Product

Resources

About