Journal
MOLECULAR NEUROBIOLOGY
Volume 51, Issue 3, Pages 864-877Publisher
SPRINGER
DOI: 10.1007/s12035-014-8731-8
Keywords
Amyotrophic lateral sclerosis; Cell death by apoptosis; Glycoursodeoxycholic acid; Matrix metalloproteinase-9 activation; Mitochondrial dysfunction; Motor neuron degeneration; NSC-34 cells expressing the human SOD1(G93A) mutation
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Funding
- FEDER (COMPETE Program)
- National funds (Fundacao para a Ciencia e a Tecnologia-FCT) [PTDC/SAU-FAR/118787/2010, PEst-OE/SAU/UI4013/2011-2013]
- FCT [SFRH/BD/91316/2012]
- [SFRH/BPD/76590/2011]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/91316/2012, PTDC/SAU-FAR/118787/2010, SFRH/BPD/76590/2011] Funding Source: FCT
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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 (hSOD1(G93A)) 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/hSOD1(G93A) 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 mu M GUDCA at 0 DIV and at 2 DIV, respectively. Increased cytosolic SOD1 inclusions were observed in 4 DIV NSC-34/hSOD1(G93A) 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/hSOD1(G93A) 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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