SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system
© Watanabe et al. 2014
Received: 2 July 2014
Accepted: 14 August 2014
Published: 29 August 2014
Dominant mutations in superoxide dismutase 1 (SOD1) cause degeneration of motor neurons in a subset of inherited amyotrophic lateral sclerosis (ALS). The pathogenetic process mediated by misfolded and/or aggregated mutant SOD1 polypeptides is hypothesized to be suppressed by protein refolding. This genetic study is aimed to test whether mutant SOD1-mediated ALS pathology recapitulated in mice could be alleviated by overexpressing a longevity-related deacetylase SIRT1 whose substrates include a transcription factor heat shock factor 1 (HSF1), the master regulator of the chaperone system.
We established a line of transgenic mice that chronically overexpress SIRT1 in the brain and spinal cord. While inducible HSP70 (HSP70i) was upregulated in the spinal cord of SIRT1 transgenic mice (PrP-Sirt1), no neurological and behavioral alterations were detected. To test hypothetical benefits of SIRT1 overexpression, we crossbred PrP-Sirt1 mice with two lines of ALS model mice: A high expression line that exhibits a severe phenotype (SOD1G93A-H) or a low expression line with a milder phenotype (SOD1G93A-L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1G93A-L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1G93A-L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1G93A-L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1G93A-H transgenic mice partly because their HSP70i level had peaked out.
The genetic supplementation of SIRT1 can ameliorate a mutant SOD1-linked ALS mouse model partly through the activation of the HSF1/HSP70i chaperone system. Future studies shall include testing potential benefits of pharmacological enhancement of the deacetylation activity of SIRT1 after the onset of the symptom.
KeywordsSirtuin 1 (SIRT1) Cu/Zn-superoxide dismutase (SOD1) Heat shock factor 1 (HSF1) Heat shock protein (HSP) Amyotrophic lateral sclerosis (ALS) Systematic behavioral screening
Pathological protein aggregation is a major hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease and polyglutamine diseases . In ALS, approximately 10% is inherited and about 20% of the inherited ALS are caused by dominant mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) . Many of ALS causative SOD1 mutants retain the enzymatic activity for catalyzing superoxide anion to hydrogen peroxide and deletion of wild-type SOD1 from mice does not cause ALS phenotype, suggesting that SOD1 mutants provoke motor neuron degeneration through “gain of toxic function” mechanisms . It has been suggested that altered conformations of mutant SOD1 proteins are linked to the toxicity . Recent studies demonstrated that accumulation of misfolded SOD1 proteins is not only specific to SOD1-related familial ALS but also involved in a subset of sporadic ALS ,.
Chaperone system is a major cytoprotective mechanism against proteotoxic stresses. Unfolded or misfolded proteins are restored to their proper conformations with the help of heat shock proteins (HSPs) including HSP110/105, constitutive and inducible HSP70s (HSC70, HSP70i). HSP110/105, HSP70i, and HSP40 directly bind to mutant SOD1 and facilitate the clearance of SOD1 through the ubiquitin-proteasome pathway –, suggesting that HSPs are involved in the neuroprotective mechanisms against SOD1-mediated neurodegeneration. Indeed, HSP70i co-expression in motor neurons substantially inhibits the SOD1-aggregation and improves the cell viability . Moreover, HSP70i is also effective against other neurodegenerative diseases, such as Parkinson’s disease  and Alzheimer’s disease . These data suggest that the induction of HSPs is a promising therapeutic strategy for neurodegenerative diseases including ALS.
Upon exposure to proteotoxic stresses, heat shock factor 1 (HSF1) forms a trimer, translocates to the nucleus, binds to regulatory elements of DNA, and upregulates a set of genes including HSP70i whose products constitute the chaperone system . Deacetylation of HSF1, which is mediated partly by a sirtuin family deacetylase SIRT1, prolongs its binding to the heat shock promoters . Recent studies have demonstrated beneficial effects of resveratrol, which is considered to potentiate the sirtuin cascade, on SOD1-ALS models ,. Given the pleiotropic effect of resveratrol through non-sirtuin targets, the role of SIRT1 in motor neuron degeneration is to be examined. However, the effect of genetic supplementation of SIRT1 in ALS mice has never been directly tested.
On the basis of the above background, in this study we establish transgenic mouse lines that express SIRT1 in the central nervous system (CNS) under control of the murine prion promoter (PrP). We find that modest overexpression of SIRT1 alone does not cause neurological and behavioral alterations. To test the effects of SIRT1 overexpression, we crossbred the line with either of the two lines of transgenic mice which express a high and a low dose of the toxic SOD1G93A polypeptide that recapitulate selective motor neuron degeneration. We find that SIRT1 overexpression consistently endows partial rescue effects with the milder ALS model with the lower dose of SOD1G93A. Biochemical analysis of the spinal cord extracts reveals upregulation of HSP70i and reduced aggregation of SOD1G93A in the SOD1G93A/PrP-Sirt1 mice, corroborating the beneficial role of SIRT1 partly through activating the HSF1/HSP70i system.
Generation of a prion promoter-driven Sirt1 transgenic mouse
Chronic overexpression of SIRT1 in the CNS does not affect the behavior of mice
Summary of systematic behavioral tests for PrP-Sirt1 mice in comparison with wild-type littermates
Alteration from wild type
General health and neurological screening
(Additional file 1: Figure S3)
Light/dark transition test
Distance traveled in the light chamber
(Additional file 1: Figure S4)
Distance traveled in the dark chamber
Latency to the first entry to the light chamber
Time stayed in the light chamber
Number of transitions between chambers
Open field test
(Additional file 1: Figure S5)
Avoidance from open space
Elevated plus maze test
(Additional file 1: Figure S6)
Entries into open arms
Number of entries
Time stayed on open arms
Acoustic startle response
Startle reflex to loudness
Ampliture of body motion
(Additional file 1: Figure S7A)
Prepulse inhibition (PPI) test
Decrement of startle amplitude
(Additional file 1: Figure S7B)
Porsolt forced swim test
Latency to immobility
(Additional file 1: Figure S8)
Home cage monitoring
Diurnal cycle of locomotor activity
Activity level (distance traveled)
(Additional file 1: Figure S9)
Mean number of particles
Social interaction test
Social behavior, anxiety-like behavior
(1 chamber, stranger pair)
Number of contacts
(Additional file 1: Figure S10)
Total duration of active contacts
Mean contact duration
Total duration of contacts
Social interaction test
Social behavior, anxiety-like behavior
Time spent with novel stranger
↓ (Step 2)
(3 chamber, 1–2 caged strangers)
(Additional file 1: Figure S11)
Latency to fall
(Additional file 1: Figure S12)
Mechanics of limb movement
Limb positions and timings
→ (front step angle)
(Additional file 1: Figure S13)
↑ (hind step angle)
Hot plate test
Aversive response to noxious stimulus
Latency to limb withdrawal
(Additional file 1: Figure S14)
Tail suspension test
Latency to immobility
(Additional file 1: Figure S15)
Time spent around each hole
(Additional file 1: Figure S16)
Fear conditioning test
(Additional file 1: Figure S17)
Cued test with altered context
Endogenous SIRT1 is upregulated in the spinal cord of SOD1G93A and SOD1G37R transgenic mouse
SIRT1 overexpression extends lifespan of the transgenic mouse expressing low copy of SOD1G93A
SIRT1 overexpression causes deacetylation of HSF1, upregulation of HSP70i, and reduction of misfolded SOD1G93A
In this study, we established a line of transgenic mice that chronically overexpress SIRT1 in the brain and spinal cord. As expected, overexpression of SIRT1 gave partial rescue effect on SOD1G93A mice. Supplementation of SIRT1 in the CNS slowed the disease progression and extended the lifespan of SOD1G93A-L mice with a reduction of misfolded/aggregated SOD1 presumably through the activation of the HSF1/HSP70i pathway.
Previous reports from other groups showed that SIRT1 overexpression causes deficits in reference memory in the novel object recognition test , voluntary movement in the open field test, and motor coordination in the rotating rod test . In contrast, we detected no significant neurological or behavioral differences between PrP-Sirt1 mice and their non-transgenic littermates with a few minor exceptions (Table 1, Additional file 1: Figure S3-S17). The discrepancy might be due to the transgene constructions, genomic position effects, and epigenetic factors that affect the levels and spatiotemporal patterns of expression. Our PrP-Sirt1 mice with minimal neurological deficits are suitable for testing the effects of SIRT1 supplementation on various models of neurological disorders. In fact, their remarkable resistance against cerebral hypoperfusion has been demonstrated with a bilateral carotid artery stenosis model .
The beneficial role of SIRT1 has been demonstrated in various neurodegenerative disease models. Neuroprotective effects of SIRT1 have been reported in Huntington’s disease ,, Parkinson’s disease , Alzheimer’s disease ,, and spinal and bulbar muscular atrophy . In this study, we demonstrated that SIRT1 overexpression has partial protective effects on a mouse ALS model. Previous studies showed that resveratrol, an activator of SIRT1, extended the lifespan of SOD1G93A mice ,. However, given the pleiotropic effects of resveratrol through other target proteins, our results provide the first direct evidence for the contribution of SIRT1 to the alleviation of neurodegeneration in the ALS model.
Our findings suggest that the beneficial effects of SIRT1 depend at least in part on the HSF1/HSP70i pathway. This is consistent with a previous study demonstrating that HSF1 overexpression is partially protective against SOD1-mediated toxicity through the induction of HSP70i and αB-crystallin . On the other hand, it should be noted that this study does not exclude possible involvement of other downstream effectors of SIRT1, such as PGC-1α , or p53, in the neuroprotective effects.
HSP70i reduces Triton X-100-insoluble SOD1 species (Figure 5C)  and exogenously delivered HSP70i extends the lifespan of SOD1G93A mice . Although it is unknown whether the mutant SOD1 proteins are refolded, degraded or both in each case, these data suggest the reduction of toxic SOD1 species contributes to the amelioration of SOD1-linked ALS model mice by inducing HSP70i. Since endogenous chaperone system was not sufficiently activated in SOD1-linked ALS model mice (Figure 2C) , supplementation of HSPs would be a promising means to cope with the proteotoxicity of mutant SOD1. Another study showed that HSP70i overexpression does not ameliorate the symptom and pathology of SOD1G93A, SOD1G37R, and SOD1G85R transgenic mouse lines . We speculate that the differences come from the severity of the models. As we demonstrated, SIRT1 overexpression was effective for the rescue of SOD1G93A-L but not of SOD1G93A-H (Figure 3), whose levels of HSP70i in the end stage were comparable (Additional file 1: Figure S1). These findings suggest that the refolding capacity of HSP70i against the toxicity of mutant SOD1 is limited, especially in the presence of excess amounts of misfolded proteins by overexpression of transgene.
We have previously demonstrated that E6-associated protein (E6-AP), a dual function steroid hormone receptor coactivator and ubiquitin-protein ligase, is involved in SOD1 aggresome degradation and suppresses mutant SOD1-mediated toxicity . Interestingly, E6-AP ubiquitinates the misfolded proteins that are bound to HSC70 , and co-expression of E6-AP and HSC70 gives more potent neuroprotection . It is also known that C-terminus of HSP70-interacting protein (CHIP) is involved in misfolded protein degradation through the ubiquitin-proteasome system ,. These observations suggest that the chaperone system and the ubiquitin-proteasome system are closely coordinated to cope with the proteotoxic stress. Proteasomal function is inhibited by mutant SOD1 , and the expression of HSP70i has peaked out at the end stage of the disease even in the case of SOD1G93A-L (Additional file 1: Figure S1). These data suggest that accumulation of proteotoxic species caused by proteasomal dysfunction could readily excess the capacity of the chaperone system. Therefore, coordinated activation of the chaperone system and protein degradation systems that include the ubiquitin-proteasome system and the autophagy system is critical to cope with the proteotoxicity of mutant SOD1 or other causative proteins of neurodegenerative diseases.
The genetic supplementation of SIRT1 can ameliorate a mutant SOD1-linked ALS mouse model partly through the positive regulation of the HSF1/HSP70i chaperone system. Future studies shall include identifying other downstream effectors and testing potential benefits of pharmacological enhancement of the deacetylation activity of SIRT1 after the onset of the symptom.
Materials and Methods
Generation of SIRT1 transgenic mice and crossbreeding with mutant SOD1 mice
To generate a line of transgenic mice that chronically overexpress SIRT1 in the central nervous system, we constructed a transcription unit by inserting the coding region of the mouse Sirt1 cDNA into the MoPrP (mouse prion gene promoter)-polyA cassette (Figure 1A) . We injected linearized MoPrP-Sirt1 transcription unit with a genetic marker (mouse αA-crystallin promoter-driven enhanced green fluorescent protein (EGFP)) into C57BL/6 J mouse oocytes and obtained a founder that transmitted the transgene in Mendelian manner. The genotyping was done by polymerase chain reaction for an artificial sequence near the MoPrP-Sirt1 junction. The transgenic line is to be deposited to RIKEN Bioresource Center. Sirt1 transgenic and non-transgenic control mice for behavioral analyses were bred as littermates. Transgenic mouse lines expressing human SOD1 gene with ALS-linked mutations, SOD1G93A-H [B6.Cg-Tg(SOD1*G93A)1Gur/J] or loxSOD1G37R [B6.Cg-Tg(SOD1-G37R) 1Dwc/J] were previously described ,. SOD1G93A-L was generated by a spontaneous drop of the copy number of the SOD1G93A-H line, and has been maintained in our laboratory for several generations.
Animals and experimental design
All animal procedures were conducted in accordance with the guidelines of the Animal Use and Care Committees of Kyoto University, National Institute for Physiological Science, Nagoya University, and RIKEN. All comparisons were made between littermates to minimize confounding effects of different genetic background and environment. All behavioral tests were conducted at 5–9 months of age as described previously ,. Mice were group housed (4 mice per cage) in a specific pathogen-free room kept at 23 ± 2°C with a 12 h light/dark cycle (lights on at 7 a.m.) with access to food and water. For survival experiments, SOD1G93A mice were always compared with their littermates with PrP-Sirt1 gene. Times of disease onset, early phase, and end stage were determined respectively as the time when mice had started losing the maximum body weight, when denervation-induced muscle atrophy had produced a 10% loss of maximal weight, and when animals in lateral position failed in righting within 20 seconds, an endpoint commonly used for mutant SOD1 expressing mice which is compliant with the requirements of the Animal Use and Care Committee. Disease progression was defined by the duration between the onset and disease end-stage. Statistical analysis of survival time and disease duration was performed with a log-rank test and one-way ANOVA following post-hoc t-tests, respectively. Analyses were carried out by using GraphPad Prism (GraphPad Software, La Jolla, CA).
Genotyping of mice
Mice harboring PrP-Sirt1 transgene were identified by PCR using following primers; 5′-CAAGAGGTTGTTAATGAAGC-3′ and 5′-TTTCCTGTTGCCTTCAATCAGCTATCG-3′.
Mice harboring SOD1G93A or SOD1G37R transgene were identified by PCR using following primers; the mouse SOD1 gene fragment (850 bp) was amplified by mSOD-A primer: 5′-GTTACATATAGGGGTTTACTTCATAATCTG-3′ and h/mSOD-C primer: 5′-CAGCAGTCACATTGCCCARGTCTCCAACATG-3′, and human SOD1 gene fragment (750 bp) was amplified by hSOD-B primer: 5′-CCAAGATGCTTAACTCTTGTAATCAATGGC-3′ and h/mSOD-C primer.
We used the following commercially available antibodies: anti-SIRT1 from EMD Millipore Corp. (Billerica, MA, USA), anti-β-actin from Sigma-Aldrich Co. LLC. (St. Louis, MO, USA), anti-acetylated lysine from Cell Signaling Technology Inc. (Danvers, MA, USA), anti-HSF1, anti-HSP70i and anti-HSP90 from Enzo Life Sciences Inc. (Farmingdale, NY, USA). Rabbit anti-human SOD1 antibody was raised against a recombinant human SOD1 peptide (24–36) and purified with protein A .
Tissues were homogenized in TNE lysis buffer [50 mM Tris–HCl (pH 7.4), 150 mM NaCl, 1 mM ethylenediaminetetraacetic acid (EDTA), 1% Triton-X 100, protease inhibitor cocktail (Roche, Basel, Switzerland)] with Dounce homogenizer. The lysates were centrifuged at 15,000 × g for 10 min at 4°C and the supernatants were collected. For the analyses of insoluble SOD1, the pellets were re-solubilized in the equivalent volume of TNE lysis buffer supplemented with 2% SDS and benzonase (Roche). After minutes of incubation at room temperature, the lysates were sonicated and centrifuged at 15,000 × g for 10 min. The supernatants were collected as insoluble fractions. All the protein content was measured by micro BCA assay kit (Thermo Fisher Scientific Inc., Waltham, MA, USA) and equal amounts of total proteins were analyzed by immunoblotting. Densitometric analysis was performed after the chemiluminescence detection by using an image analyzer LAS-4000mini (Fuji film, Tokyo, Japan) with the equipped software.
For the detection of HSF1 deacetylation, we slightly modified the previously reported procedure . In brief, lumbar spinal cords were homogenized in radioimmunoprecipitation (RIPA) buffer [50 mM Tris–HCl (pH 8.0), 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS] supplemented with 1 mM EDTA, 2 mM nicotinamide and 1 mM trichostatin A (all from Sigma) with Dounce homogenizer. The lysates were centrifuged at 15,000 × g for 10 min at 4°C. Anti-HSF1 antibody (1:100) was added to the supernatant and incubated for over-night at 4°C with gentle agitation. Protein G sepharose (GE Healthcare, Waukesha, WI, USA; 15 μl each) was added and incubated for further 1.5 h. The beads were washed four times with phosphate buffered saline. The proteins were eluted with 2 × SDS loading buffer and heating at 95°C for 3 min. Deacetylated and total HSF1 were detected on the same polyvinylidene difluoride membrane with Restore western blot stripping buffer (Thermo).
amyotrophic lateral sclerosis
central nervous system
enhanced green fluorescent protein
heat shock factor 1
heat shock protein
inducible heat shock protein 70
standard error of the mean
SOD1G93A high expression line
SOD1G93A low expression line
sodium dodecyl sulfate
We thank D. Borchelt (University of Florida) for Mo-Prp DNA, S. Imai (Washington University) for mouse Sirt1 cDNA, A. Cvekl (Albert Einstein College of Medicine) for mouse αA-crystallin promoter DNA, and A. Tanigaki, R. Hikawa, C. Oshima, and H. Tsuiji for technical help in the establishment and/or analysis of the PrP-Sirt1 transgenic lines. This work was supported in part by CREST (Creation of a novel technology for prevention, diagnosis, and therapy for psychiatric and neurological disorders) from JST, Grant-in-Aid for Scientific Research on Innovative Areas (Foundation of Synapse Neurocircuit Pathology) (to MK and KY), Comprehensive Brain Science Network, and Grants-in-Aid for Scientific Research 23111006 (to KY), 22700404 (to SW) from the Ministry for Education, Culture, Sports and Science and Technology, Japan, and Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labor and Welfare of Japan, and Naito Foundation.
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