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Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1G93A) Mouse Model of ALS

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. ALS neuropathology is associated with increased oxidative stress, excitotoxicity, and inflammation. We and others reported that the anti-aging and cognition-enhancing protein Klotho is a neuroprotective, antioxidative, anti-inflammatory, and promyelinating protein. In mice, its absence leads to an extremely shortened life span and to multiple phenotypes resembling human aging, including motor and hippocampal neurodegeneration and cognitive impairment. In contrast, its overexpression extends life span, enhances cognition, and confers resistance against oxidative stress; it also reduces premature mortality and cognitive and behavioral abnormalities in an animal model for Alzheimer’s disease (AD). These pleiotropic beneficial properties of Klotho suggest that Klotho could be a potent therapeutic target for preventing neurodegeneration in ALS. Klotho overexpression in the SOD1 mouse model of ALS resulted in delayed onset and progression of the disease and extended survival that was more prominent in females than in males. Klotho reduced the expression of neuroinflammatory markers and prevented neuronal loss with the more profound effect in the spinal cord than in the motor cortex. The effect of Klotho was accompanied by reduced expression of proinflammatory cytokines and enhanced the expression of antioxidative and promyelinating factors in the motor cortex and spinal cord of Klotho × SOD1 compared to SOD1 mice. Our study provides evidence that increased levels of Klotho alleviate ALS-associated pathology in the SOD1 mouse model and may serve as a basis for developing Klotho-based therapeutic strategies for ALS.

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Abbreviations

ADAM:

A disintegrin and metalloprotease domain

ALS:

Amyotrophic lateral sclerosis

ALS TDI:

ALS Therapy Development Institute

AD:

Alzheimer’s disease

Axin 2:

Axin-related protein 2

AHCs:

Anterior horn cells

C9ORF72:

Chromosome 9 open reading frame 72

CSF:

Cerebrospinal fluid

CCR2:

C-C chemokine receptor type 2

Cox-2:

Cyclooxygenase-2

FALS:

Familial amyotrophic lateral sclerosis

FGFR:

Fibroblast growth factor receptors

FOXO:

Forkhead box O

Fzd5:

Frizzled gene family encoding 7-transmembrane domain proteins

GFAP:

Glial fibrillary acidic protein

HBSS:

Hank’s balanced salt solution

Iba1:

Ionized calcium-binding adaptor molecule 1

KL-OE:

Klotho-overexpressing

IGF-1:

Insulin-like growth factor 1

IHC:

Immunohistochemistry

IL-1α:

Interleukin-1α

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-10:

Interleukin-10

IL-12a:

Interleukin-12a

iNOS:

Inducible nitric oxide synthase

MAG:

Myelin-associated glycoprotein

MBP:

Myelin basic protein

MN:

Motor neurons

MS:

Multiple sclerosis

Prx-2:

Peroxiredoxin-2

Prx-3:

Peroxiredoxin-3

PLP1:

Proteolipid protein 1

rmKL:

Recombinant mouse Klotho

NeuN:

Neuronal nuclei

NF-κB:

Nuclear factor-κB

NOS:

Nitric oxide synthase

Nrf2:

Nuclear factor erythroid 2-related factor 2

NS:

Neurological score

SMAD:

The activated type I receptors interact with and phosphorylate SMAD (an acronym for the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad) proteins to transduce signals

SOD:

Superoxide dismutase

TDP-43:

TAR DNA-binding protein 43

TGF-β:

Transforming growth factor-β

TNF-α:

Tumor necrosis factor-α

TNFAIP2:

TNF alpha-induced protein 2

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

VEGF:

Vascular endothelial growth factor

Wnt:

Wnt is an acronym that stands for “Wingless/Integrated”

WT:

Wild type

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Acknowledgments

The authors wish to thank Dr. Douglas Rosene for his help with statistical analysis.

Funding

This work was supported by NIH grants R01-AG052465 to NCL and R56-AG051638 to CRA.

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Authors and Affiliations

  1. Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA

    Ella Zeldich, Ci-Di Chen, Emma Boden, Jason S. Nasse, Qicheng Ma, Nelson C. Lau & Carmela R. Abraham

  2. Klogene Therapeutics, Inc., Boston, MA, USA

    Ella Zeldich, Ci-Di Chen, Andrea Yuste & Carmela R. Abraham

  3. Department of Biomedical Engineering, Boston University, Boston, MA, USA

    Bryce Howat, Dean Zeldich & Anthony G. Lambert

  4. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Jonathan D. Cherry, Rebecca M. Mathias & Ann C. McKee

  5. Veterans Administration Boston Healthcare System, Boston, MA, USA

    Rebecca M. Mathias & Ann C. McKee

  6. Genome Science Institute, Boston University School of Medicine, Boston, MA, USA

    Nelson C. Lau

  7. Department of Pathology, Boston University School of Medicine, Boston, MA, USA

    Ann C. McKee

  8. ALS Therapy Development Institute, Cambridge, MA, USA

    Theo Hatzipetros

  9. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Carmela R. Abraham

Authors
  1. Ella Zeldich
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  2. Ci-Di Chen
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  3. Emma Boden
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  4. Bryce Howat
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  10. Rebecca M. Mathias
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  11. Qicheng Ma
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  12. Nelson C. Lau
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  15. Carmela R. Abraham
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Contributions

EZ, CDC, and CRA conceived the project. EZ, TH, and CRA designed the study. EZ, CDC, EB, BH, JSN, DZ, AGL, and AY performed the experiments in the laboratory of CRA and JDC and RMM in the laboratory of ACM. NCL and QM participated in the RNAseq analyses. All authors contributed to the analyses and/or interpreted the data. EZ wrote the paper with contributions from JSN, TH, and CRA. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Carmela R. Abraham.

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All animal procedures were performed in accordance with a protocol approved by the Boston University Institutional Animal Care and Use Committee.

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Zeldich, E., Chen, CD., Boden, E. et al. Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1G93A) Mouse Model of ALS. J Mol Neurosci 69, 264–285 (2019). https://doi.org/10.1007/s12031-019-01356-2

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