The voltage-gated calcium channel blocker lomerizine is neuroprotective in motor neurons expressing mutant SOD1, but not TDP-43.
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 SOD1. 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 SOD1 toxicity: Ca(2+) overload, impaired mitochondrial trafficking, mitochondrial fragmentation, formation of mutant SOD1 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 SOD1 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.
Department of Neurology/Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Luan T
LT
Tran
Benoit J
BJ
Gentil
Kathleen E
KE
Sullivan
Heather D
HD
Durham
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D018014:Gene Transfer Techniques; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000502:physiology; D018696:Neuroprotective Agents; D010879:Piperazines / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics* / Q000502:physiology*; D000072105:Superoxide Dismutase-1
D002118:Calcium; D002121:Calcium Channel Blockers; D004268:DNA-Binding Proteins; D018696:Neuroprotective Agents; D010879:Piperazines; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000606290:SOD1 protein, human; C578077:Tardbp protein, mouse; C052424:lomerizine; C000606291:Sod1 protein, mouse
FUS; SOD1; TDP-43; amyotrophic lateral sclerosis; lomerizine; voltage-gated calcium channel