Premium
The voltage‐gated calcium channel blocker lomerizine is neuroprotective in motor neurons expressing mutant SOD 1, but not TDP ‐43
Author(s) -
Tran Luan T.,
Gentil Benoit J.,
Sullivan Kathleen E.,
Durham Heather D.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12738
Subject(s) - excitotoxicity , neuroprotection , microbiology and biotechnology , chemistry , glutamate receptor , voltage dependent calcium channel , riluzole , pharmacology , nmda receptor , ampa receptor , biology , biochemistry , receptor , calcium , organic chemistry
Excitotoxicity and disruption of Ca 2+ homeostasis have been implicated in amyotrophic lateral sclerosis ( ALS ) and limiting Ca 2+ entry is protective in models of ALS caused by mutation of SOD 1 . Lomerizine, an antagonist of L‐ and T‐type voltage‐gated calcium channels and transient receptor potential channel 5 transient receptor potential channels, is well tolerated clinically, making it a potential therapeutic candidate. Lomerizine reduced glutamate excitotoxicity in cultured motor neurons by reducing the accumulation of cytoplasmic Ca 2+ and protected motor neurons against multiple measures of mutant SOD 1 toxicity: Ca 2+ overload, impaired mitochondrial trafficking, mitochondrial fragmentation, formation of mutant SOD 1 inclusions, and loss of viability. To assess the utility of lomerizine in other forms of ALS , calcium homeostasis was evaluated in culture models of disease because of mutations in the RNA ‐binding proteins transactive response DNA ‐binding protein 43 ( TDP ‐43) and Fused in Sarcoma ( FUS ). Calcium did not play the same role in the toxicity of these mutant proteins as with mutant SOD 1 and lomerizine failed to prevent cytoplasmic accumulation of mutant TDP ‐43, a hallmark of its pathology. These experiments point to differences in the pathogenic pathways between types of ALS and show the utility of primary culture models in comparing those mechanisms and effectiveness of therapeutic strategies.Calcium sensitivity is a factor in motor neuron vulnerability in ALS. The voltage‐gated calcium channel blocker lomerizine normalized [Ca 2+ ] and reduced toxicity of mutant Cu/Zn‐superoxide dismutase (SOD1) causing familial ALS1. Calcium homeostasis was not disrupted in motor neurons expressing ALS‐associated mutants of TAR DNA‐binding protein 43 (TDP‐43) or FUS, nor was lomerizine protective, affirming differences in pathogenic mechanism and therapeutic efficacy in the forms of ALS.