Fast axonal transport in amyotrophic lateral sclerosis

Breuer, Anthony C.; Lynn, Marc P.; Atkinson, M; Chou, Shih-Ching; Wilbourn, Asa J.; Marks, K.E.; Culver, Joe; Fleegler, E. J.

doi:10.1212/wnl.37.5.738

Cited by 84 publications

(49 citation statements)

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“…Because this study shows that mutant SOD1 is sequestered to form large inclusions by interacting with dynein, it is logical to propose that the mutant SOD1-dynein interaction could also interfere with the dynein-mediated axonal transport in ALS. Impaired axonal transport, but not a complete inhibition of transport, has been reported in both ALS patients and animal models (47)(48)(49)(50)(51)(52). However, the mechanisms underlying this impairment are unclear.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation

Ström

Shi

Zhang

et al. 2008

Journal of Biological Chemistry

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An important consequence of protein misfolding related to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), is the formation of proteinaceous inclusions or aggregates within the central nervous system. We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interact and co-localize with the dynein-dynactin complex in cultured cells and affected tissues of ALS mice. In this study, we report that the interaction between mutant SOD1 and the dynein motor plays a critical role in the formation of large inclusions containing mutant SOD1. Disruption of the motor by overexpression of the p50 subunit of dynactin in neuronal and non-neuronal cell cultures abolished the association between aggregation-prone SOD1 mutants and the dynein-dynactin complex. The p50 overexpression also prevented mutant SOD1 inclusion formation and improved the survival of cells expressing A4V SOD1. Furthermore, we observed that two ALS-linked SOD1 mutants, H46R and H48Q, which showed a lower propensity to interact with the dynein motor, also produced less aggregation and fewer large inclusions. Overall, these data suggest that formation of large inclusions depends upon association of the abnormal SOD1s with the dynein motor. Whether the misfolded SOD1s directly perturb axonal transport or impair other functional properties of the dynein motor, this interaction could propagate a toxic effect that ultimately causes motor neuron death in ALS. Amyotrophic lateral sclerosis (ALS)2 is a progressive and fatal neurodegenerative disease primarily affecting motor neurons in the spinal cord and brainstem. Approximately 10% of ALS cases are inherited, and of these ϳ20% are caused by mutations in the Cu,Zn-superoxide dismutase 1 (SOD1) gene (1, 2). To date, more than 100 mutations scattered throughout the SOD1 protein have been identified (3). Many SOD1 mutants retain nearly normal enzymatic activity, and SOD1 knock-out mice do not develop ALS (4, 5). Therefore, it is believed that mutant SOD1s acquire a toxic "gain-of-function" property.We recently identified dynein as a component of soluble SOD1-containing high molecular weight (HMW) complexes (6), which have been implicated in neuronal toxicity and may be precursors to SOD1 inclusions (7-9). Moreover, co-immunoprecipitation using tissue lysates from transgenic rodents expressing wild-type (WT), G93A, or G85R SOD1, showed that mutant SOD1 interacted with the dynein-dynactin complex to a much greater extent than did WT SOD1. The association was detected in the pre-symptomatic G93A mice (60 days), and the amount of mutant SOD1 interacting with the dynein complex increased over the disease progression (6).Dynein-mediated microtubule-dependent retrograde transport has been shown to be important for sequestration of misfolded proteins into large inclusions called aggresomes (10,11). We hypothesized that the interaction between the dynein motor and mutant SOD1 could play a role in the aggregation and formation of inc...

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Section: Discussionmentioning

confidence: 99%

Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation

Ström

Shi

Zhang

et al. 2008

Journal of Biological Chemistry

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“…Several clinical manifestations of impaired hsp functions have now been described, including mutations in the family of small heat shock protein members hsp22 and Hsp27, which have been linked to a motor-specific form of familiar Charcot-Marie-Tooth Disease [9]. Furthermore, perturbed hsp expression has also been linked to several pathophysiological mechanisms, so that for example, mutations in hsp22 and hsp27 are known to disrupt axonal transport [10]. Interestingly, defects in axonal transport have been linked to motoneuron degeneration in both mouse models of ALS and ALS patients [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Kalmár¹,

Greensmith²

2009

Cellular and Molecular Biology Letters

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Abbreviations used: ALS -Amyotrophic Lateral Sclerosis; HSF-1 -heat shock factor-1; hsp -heat shock protein; HSR -heat shock response Research article ACTIVATION OF THE HEAT SHOCK RESPONSE IN A PRIMARY CELLULAR MODEL OF MOTONEURON NEURODEGENERATION -EVIDENCE FOR NEUROPROTECTIVE AND NEUROTOXIC EFFECTSBERNADETT KALMAR* and LINDA GREENSMITH Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United KingdomAbstract: Pharmacological up-regulation of heat shock proteins (hsps) rescues motoneurons from cell death in a mouse model of amyotrophic lateral sclerosis. However, the relationship between increased hsp expression and neuronal survival is not straightforward. Here we examined the effects of two pharmacological agents that induce the heat shock response via activation of HSF-1, on stressed primary motoneurons in culture. Although both arimoclomol and celastrol induced the expression of Hsp70, their effects on primary motoneurons in culture were significantly different. Whereas arimoclomol had survival-promoting effects, rescuing motoneurons from staurosporin and H 2 O 2 induced apoptosis, celastrol not only failed to protect stressed motoneurons from apoptosis under same experimental conditions, but was neurotoxic and induced neuronal death. Immunostaining of celastrol-treated cultures for hsp70 and activated caspase-3 revealed that celastrol treatment activates both the heat shock response and the apoptotic cell death cascade. These results indicate that not all agents that activate the heat shock response will necessarily be neuroprotective.

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“…Second, ALS primarily affects motor neurons, which are among the largest neurons in the body and should therefore be particularly vulnerable to transport deficits. Finally, abnormalities of organelle transport in ALS animal models (7,8,16), and even in humans suffering from ALS (17), are well documented in vitro and in vivo.…”

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confidence: 99%

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.

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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.

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Fast axonal transport in amyotrophic lateral sclerosis

Cited by 84 publications

References 0 publications

Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation

Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

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

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