A mutation in the dynein heavy chain gene compensates for energy deficit of mutant SOD1 mice and increases potentially neuroprotective IGF-1
© Fergani et al; licensee BioMed Central Ltd. 2011
Received: 2 December 2010
Accepted: 26 April 2011
Published: 26 April 2011
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. ALS patients, as well as animal models such as mice overexpressing mutant SOD1s, are characterized by increased energy expenditure. In mice, this hypermetabolism leads to energy deficit and precipitates motor neuron degeneration. Recent studies have shown that mutations in the gene encoding the dynein heavy chain protein are able to extend lifespan of mutant SOD1 mice. It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects.
SOD1(G93A) mice were crossbred with mice harboring the dynein mutant Cramping allele (Cra/+ mice). Dynein mutation increased adipose stores in compound transgenic mice through increasing carbohydrate oxidation and sparing lipids. Metabolic changes that occurred in double transgenic mice were accompanied by the normalization of the expression of key mRNAs in the white adipose tissue and liver. Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting. In SOD1(G93A) mice, the dynein Cra mutation led to increased expression of IGF-1 in the liver, increased systemic IGF-1 and, most importantly, to increased spinal IGF-1 levels that are potentially neuroprotective.
These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons in the motor cortex, brainstem and spinal cord. ALS patients develop progressive muscle weakness and paralysis leading to death 3 to 5 years after first symptoms. Despite most cases of ALS occur sporadically, 5% are genetically inherited. Out of these familial forms of ALS, a subset is caused by mutations in the gene encoding the Cu/Zn-superoxide dismutase 1 (SOD1).
Studies on patients and transgenic mutant SOD1 mice showed that ALS-linked neurodegeneration was usually associated with defects in energy homeostasis . Indeed, mutant SOD1 mice show a pronounced hypermetabolism characterized by weight loss, increased oxygen consumption and an increased use of lipids stores [2, 3]. In sporadic ALS patients, hyperlipemia was associated with increased survival [4, 5]. The mechanisms by which such changes in energy metabolism participate to motor neuron degeneration remain unknown.
Recent studies have shown that mutations in cytoplasmic dynein heavy chain gene protect motor neurons against death and extend survival of mutant SOD1 mice [6–8]. Cytoplasmic dynein is the major molecular motor responsible for retrograde axonal transport in neurons. Three different mutations in the dynein heavy chain gene, respectively called "legs at odd angles" (Loa), "Cramping" (Cra) and "Sprawling" (Swl) have been identified in ENU-induced mouse strains [9, 10]. All three mutations lie in the stem domain of dynein heavy chain and the Loa mutation disrupts, at least partially, the dynein complex . In the nervous system, these mutations lead to perinatal proprioceptive neuropathy [8, 10, 12]. Cra/+ and Loa/+ mice are hyperactive [13, 14], and this is associated, at least in Cra/+ mice with striatal atrophy and compromised neurite outgrowth of striatal neurons . Besides the nervous system, Cra/+ and Loa/+ mice display a major phenotype in adipose tissues . Indeed, Cra/+ and Loa/+ mice show strikingly increased adipose stores, along with compromised thermogenesis. This is most likely due to defective stimulated lipolysis .
The extension in lifespan offered by mutations in dynein heavy chain gene has been attributed to several mechanisms, including compensation of axonal transport defects  and mitochondrial dysfunction , or decreased excitotoxic glutamate input to motor neurons due to degeneration of proprioceptive neurons . In this report we provide evidence that the dynein mutation is able to revert the energy deficit characteristic of ALS in mutant SOD1 mice. Interestingly, this is associated with increased hepatic IGF-1 expression and increased spinal IGF-1. Taking into account these results, we propose that the mutation in dynein is able to provide neuroprotection against SOD1-ALS through complementary pathways.
Dynein mutation compensates for energy deficit of early symptomatic transgenic SOD1(G93A) mice
Dynein mutation does not modify SOD1(G93A) hypermetabolism
Dynein mutation reverts the systemic and molecular changes associated with SOD1(G93A) energy deficit
Dynein mutation increases neuroprotective IGF-1
Our current studies provide evidence that the Cramping dynein mutation is able to revert at some point the energy deficit of SOD1(G93A) mice, and to increase IGF-1 levels in the spinal cord of SOD1(G93A) animals. These results, along with previous studies, suggest that two complementary protective pathways are acting in dynein mutant mice to provide the paradoxical protection towards SOD1(G93A) pathology.
Dynein mutation compensates for energy deficit of SOD1(G93A) mice: a rationale explanation for a seemingly paradoxical observation
This study stems from the seminal observation of a moderate lifespan extension of SOD1(G93A) mice when bearing either Loa or Cra mutation [6–8]. These studies intiated a flurry of research to explain the seemingly paradoxical observation that two distinct molecular injuries that independently lead to ALS-like disease might yield a better outcome than a single one. Indeed, dynein mutant mice were initially thought to develop motor neuron degeneration , and it appeared difficult to understand how mutating dynein, and thus precipitating late onset motor neuron degeneration, might protect against early onset SOD1(G93A)-mediated neurodegeneration. Closer examination of dynein mutant mice however refuted that they displayed motor neuron degeneration [8, 10, 12]. In the nervous system, these mice display a frank perinatal sensory neuropathy, accompanied by mild striatal atrophy in the absence of neurodegeneration . Furthermore, apart from this neuronal phenotype, dynein mutant mice also develop a number of peripheral defects, especially in brown and white adipose tissues, that are largely reminiscent of striatal degeneration diseases . The peripheral phenotype of dynein mutant mice was strikingly opposite to that of SOD1(G93A) mice. Indeed, while dynein mutant mice accumulate fats , SOD1(G93A) mice are leaner and lose white fat pads with disease progression . The origin of this energy deficit is currently unknown but is associated with increased energy expenditure. Moreover, compensating energy deficit through high fat feeding alleviates motor neuron degeneration . Importantly, these observations are of great relevance for the human pathology since lipemia is positively correlated with survival of ALS patients and energy status appears as a widely documented prognostic factor . In our hands, crossbreeding of dynein mutant mice with SOD1(G93A) mice yielded very similar effects as high fat feeding, by increasing energy storage. Increased RQ during nocturnal period suggests indirectly increased beta-oxidation, while our gene expression analysis are consistent with increased diurnal lipogenesis in compound Cra /SOD1(G93A) mice. Such a metabolic picture is fully consistent with the observed improved energy status. Thus, a straightforward interpretation would be that the dynein mutant mediated injury compensates mutant SOD1 injury through its effect on energy homeostasis, thereby alleviating neurodegeneration.
Potential involvement of IGF-1 in dynein mutant mediated protection
We further provide mechanistic insights into how the dynein mutant peripheral phenotype might provide protection to motor neurons. Liver IGF-1 expression is under the control of nutritional cues, and is for instance decreased in starved animals . Consistent with their energetic status, we observed downregulation of IGF-1 in SOD1(G93A) liver, and this was fully reverted by dynein mutation. It should be noted however that SOD1(G93A) showed only limited analogy with starved animals since liver expression of genes such as PPARα or PGC1α showed regulations opposite to those observed in starved animals. In double mutant mice, while there were no changes in circulating IGF-1, we observed increased spinal IGF-1. A similar trend was observed between wild type and SOD1(G93A) animals. One may consider that the increased hepatic production of IGF-1, due to the reversal of the energy deficit of SOD1(G93A) mice, is directed towards the nervous system, and thus motor neurons, of SOD1(G93A) mice. This is consistent with our results at the different levels at which we investigated IGF-1 (liver, skeletal muscle, plasma and spinal cord). This interpretation is further in line with modified expression of IGF-1 receptors and IGF-1 binding proteins that occur in SOD1(G93A) mice motor neurons [34, 35]. It should be noted here that circulating, liver derived IGF-1 is able to cross the blood brain barrier (BBB) and counteract age-related decline in cognitive functions [36, 37]. This natural entry might even be potentiated by leakage of the BBB during ALS disease [32, 33]. Also, IGF-1 transcytosis has been shown to be dependent upon neuronal activity, which leads to increased MMP-9 activation and cleavage of IGF binding proteins . Interestingly, we previously observed increased activity of MMP-9 in SOD1(G93A) spinal cord  and others have documented decreased levels of IGF binding proteins  in SOD1(G93A) CNS. Decreased MMP9 mRNA levels in sick SOD1(G93A) mice is not at odds with previous results since we and others have shown that MMP9 activity actually peaks before onset and then decreases [38, 39]. In all, our results support that IGF-1 transcytosis might be increased in SOD1(G93A), and to an even greater extent in Cra/SOD1(G93A) mice.
Our study does not directly address whether increased IGF-1 is responsible for the extension in lifespan. This is however plausible as most studies observed protective effect of increasing IGF-1 in SOD1(G93A) mice [23, 24]. A direct positive impact on neuromuscular junctions from circulating IGF-1 cannot be excluded since muscle-restricted expression of IGF-1 is able to stabilize neuromuscular junctions and delay motor neurons death of SOD1(G93A) G93A mice . Also, IGF-1 is able to provide protection to mitochondria even at low doses in aging rats [40, 41] through a boost in mitochondrial biogenesis and our results are thus consistent with the recent observation of mitochondrial protection in SOD1(G93A) mice by dynein mutation . In human clinical trials however, IGF-1 did not achieve efficacy in ALS clinical trials . This lack of efficacy might be due to inappropriate targeting of IGF-1 to motor neurons (see below). Alternatively, IGF-1 might be acting in combination with other still unknown circulating factors to provide full protection in dynein mutant mice. In all, we propose that circulating factors modified by the reversal of energy deficit, and between these, IGF-1, contribute to the protection offered by dynein mutation.
Mutant dynein mediated protection may rest on two complementary biological events
Several research groups, including ours, have previously shown that dynein Cra and Loa mutations were able to increase the lifespan of SOD1G93A mice. Several mechanisms have been proposed to explain the underlying mechanisms of mutant dynein protection towards mutant SOD1 pathogenesis. To conclude, we would like here to discuss critically these different hypotheses in the light of our results and provide a working model summarizing these different potential mechanisms.
In the first study, Kieran et al.  suggested a cell autonomous effect of dynein mutation in motor neurons and proposed that the defect in retrograde transport triggered by mutant dynein counterbalanced the one due to SOD1(G93A) in the anterograde direction, and thereby restoring axonal homeostasis. This cell autonomous protective effect of dynein mutation is in line with results obtained by Teuling and collaborators  that used neuron-specific overexpression of an N-terminal deleted form of BicD2 to modulate dynein/cargo interaction . Interestingly, BicD2 overexpression in neurons disrupted retrograde axonal transport, delayed the SOD1 aggregates retrograde transport toward the cell center and increased survival of SOD1 G93A mice . However, BicD2 overexpression might also have a number of dynein independent effects, including on kinesin-mediated transport  Pan-neuronal overexpression of BicD2 might also lead to impairment of neuronal physiology in neurons other than motor neurons, including in proprioceptive neurons (see below). Thus, the hypothesis of the restoration of axonal homeostasis by double blockade of both anterograde and retrograde directions of axonal transport remains unproven.
These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons. Our study provides a rationale explanation to increased survival in double dynein mutant/SOD1(G93A) mice and suggests that the neuroprotection results from dynein mutant phenotype in various tissues.
Heterozygous Cra/+ females were crossed with SOD93A males and were identified by tail DNA genotyping for the human transgene SOD1 (G93A) and the Cra mutation as described previously [7, 9]. Experiments were performed with littermates mice with 9 mice per group. Mice were maintained at 23°C with a 12h light/dark cycle and had food and water ad libitum. All animal experiments were performed under the supervision of authorized investigators and followed current EU regulations. Animals were treated in accordance with the European Union guide for the care and the use of animals in research (commission June 18th 2007, 2007/526/CE). LD has been allowed to perform mouse experiments (agreement A67-266, direction des services vétérinaires, Strasbourg, Bas-Rhin, France).
We measured O2 consumption and CO2 production by using an open-circuit indirect calorimetry system (Sable systems, Las Vegas, USA). Concentrations of O2 and CO2 in the outgoing air were successively measured in five different cages. The system was rinsed for 90 s between each measurement. Final values of gas concentrations were the mean of 10 measures obtained during 40 s. Each cage was sampled every 11 min, and one cage was left vacant as reference of ambient gas concentrations. Measurements were performed continuously over 23 1/2 h, a 30-min period being required for calibration of the O2 and CO2 analyzers. In total, 127 measures were collected per day and mouse. The average of the five lowest values of O2 consumption was considered as resting energy expenditure. Energy expenditure was obtained by using an energy equivalent of 20.1 J/ml O2. The respiratory quotient was the ratio of CO2 production over O2 consumption.
Name of the gene
Mouse IGF-1 levels were measured using Mouse/Rat IGF-I Quantikine ELISA Kit (R&D systems), using manufacturer's instructions. Plasma triglycerides and NEFAs were measured using Randox kits using manufacturer's instructions.
Statistical comparisons were accomplished with the unpaired Student t test, unless otherwise indicated, or ANOVA followed by the post hoc Newman-Keuls multiple comparisons test using PRISM version 2.0a software (GraphPad, San Diego).
List of abbreviations
alpha subunit of the nicotinic cholinergic receptor
amyotrophic lateral sclerosis
blood brain barrier
central nervous system
- Cra Cramping :
mutation of the Dyn1hc1 gene
fatty acid synthase
Insulin-like growth factor 1
copper-zinc superoxide dismutase.
This work was supported by grants from Fondation pour la Recherche Médicale, Association pour la Recherche sur la Sclérose Latérale Amyotrophique (A.R.S.) and Amyotrophic lateral sclerosis association (grant 1698) to L.D.; and Association Française contre les Myopathies, A.R.S. and Association pour la Recherche et le Développement de Moyens de Lutte contre les Maladies Neurodégénératives to J.P.L and by Deutsche Forschungsgemeinschaft (KFO142) to ACL. We acknowledge the skilful technical assistance of Marie-José Ruivo, Olivier Schandène and Annie Picchinenna. LD is supported by a grant from the "agence nationale de la recherche" (ANR) (young researcher program, Dynemit).
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