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Glycoursodeoxycholic Acid Reduces Matrix Metalloproteinase-9 and Caspase-9 Activation in a Cellular Model of Superoxide Dismutase-1 Neurodegeneration

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects mainly motor neurons (MNs). NSC-34 MN-like cells carrying the G93A mutation in human superoxide dismutase-1 (hSOD1G93A) are a common model to study the molecular mechanisms of neurodegeneration in ALS. Although the underlying pathways of MN failure still remain elusive, increased apoptosis and oxidative stress seem to be implicated. Riluzole, the only approved drug, only slightly delays ALS progression. Ursodeoxycholic acid (UDCA), as well as its glycine (glycoursodeoxycholic acid, GUDCA) and taurine (TUDCA) conjugated species, have shown therapeutic efficacy in neurodegenerative models and diseases. Pilot studies in ALS patients indicate safety and tolerability for UDCA oral administration. We explored the mechanisms associated with superoxide dismutase-1 (SOD1) accumulation and MN degeneration in NSC-34/hSOD1G93A cells differentiated for 4 days in vitro (DIV). We examined GUDCA efficacy in preventing such pathological events and in restoring MN functionality by incubating cells with 50 μM GUDCA at 0 DIV and at 2 DIV, respectively. Increased cytosolic SOD1 inclusions were observed in 4 DIV NSC-34/hSOD1G93A cells together with decreased mitochondria viability (1.2-fold, p < 0.01), caspase-9 activation (1.8-fold, p < 0.05), and apoptosis (2.1-fold, p < 0.01). GUDCA exerted preventive effects (p < 0.05) while also reduced caspase-9 levels when added at 2 DIV (p < 0.05). ATP depletion (2-fold, p < 0.05), increased nitrites (1.6-fold, p < 0.05) and metalloproteinase-9 (MMP-9) activation (1.8-fold, p < 0.05), but no changes in MMP-2, were observed in the extracellular media of 4 DIV NSC-34/hSOD1G93A cells. GUDCA inhibited nitrite production (p < 0.05) while simultaneously prevented and reverted MMP-9 activation (p < 0.05), but not ATP depletion. Data highlight caspase-9 and MMP-9 activation as key pathomechanisms in ALS and GUDCA as a promising therapeutic strategy for slowing disease onset and progression.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

DIV:

Days in vitro

fALS:

Familial amyotrophic lateral sclerosis

FBS:

Fetal bovine serum

G418:

Geneticin sulfate

GUDCA:

Glycoursodeoxycholic acid

MMPs:

Matrix metalloproteinases

MNs:

Motor neurons

mSOD1:

Mutant superoxide dismutase-1

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium

NO:

Nitric oxide

PI:

Propidium iodide

PMS:

Phenazine methosulfate

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

sALS:

Sporadic amyotrophic lateral sclerosis

SC:

Spinal cord

SOD1:

Superoxide dismutase-1

TUDCA:

Tauroursodeoxycholic acid

UDCA:

Ursodeoxycholic acid

wt:

Wild-type

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Acknowledgments

We thank Drª. Júlia Costa, Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Portugal and Prof. Neil Cashman, Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada, for the NSC-34 cells, as well as for SOD1 coding plasmids. This work was supported by FEDER (COMPETE Program) and by National funds (Fundação para a Ciência e a Tecnologia—FCT) through the projects PTDC/SAU-FAR/118787/2010 (to D.B.) and PEst-OE/SAU/UI4013/2011-2013 (to iMed.ULisboa). A.R.V. holds a postdoctoral research fellowship (SFRH/BPD/76590/2011) and C.C. is recipient of a PhD fellowship (SFRH/BD/91316/2012) from FCT. The funding organization had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare that there are no actual or potential conflicts of interest.

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  1. Research Institute for Medicines (iMed.ULisboa) and Department of Biochemistry and Human Biology, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Ana Rita Vaz & Dora Brites

  2. Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    Carolina Cunha, Cátia Gomes, Nadja Schmucki & Marta Barbosa

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  1. Ana Rita Vaz
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  2. Carolina Cunha
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Correspondence to Dora Brites.

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Vaz, A.R., Cunha, C., Gomes, C. et al. Glycoursodeoxycholic Acid Reduces Matrix Metalloproteinase-9 and Caspase-9 Activation in a Cellular Model of Superoxide Dismutase-1 Neurodegeneration. Mol Neurobiol 51, 864–877 (2015). https://doi.org/10.1007/s12035-014-8731-8

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