Laquinimod decreases Bax expression and reduces caspase-6 activation in neurons.
Laquinimod is an immunomodulatory compound that has shown neuroprotective benefits in clinical trials for multiple sclerosis. Laquinimod ameliorates both white and gray matter damage in human patients, and prevents axonal degeneration in animal models of multiple sclerosis. Axonal damage and white matter loss are a common feature shared between different neurodegenerative diseases. Caspase-6 activation plays an important role in axonal degeneration on the molecular level. Increased activity of caspase-6 has been demonstrated in brain tissue from presymptomatic Huntington disease mutation carriers, and it is an early marker of axonal dysfunction. Since laquinimod is currently undergoing a clinical trial in Huntington disease (LEGATO-HD, clinicaltrials.gov ID: NCT02215616), we set out to evaluate its impact on neuronal caspase-6 activation. We find that laquinimod ameliorates DNA-damage induced activation of caspase-6 in primary neuronal cultures. This is an indirect effect that is not mediated by direct inhibition of the enzyme. The investigation of potential caspase-6 activating mechanisms revealed that laquinimod reduces the expression of Bax, a pro-apoptotic molecule that causes mitochondrial cytochrome c release and caspase activation. Bax expression is furthermore increased in striatal tissues from the YAC128 mouse model of HD in an age-dependent manner. Our results demonstrate that laquinimod can directly downregulate neuronal apoptosis pathways relevant for axonal degeneration in addition to its known effects on astrocytes and microglia in the CNS. It targets a pathway that is relevant for the pathogenesis of HD, supporting the hypothesis that laquinimod may provide clinical benefit.
Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28(th) Avenue, Vancouver, BC, V5Z 4H4, Canada.
Dagmar E
DE
Ehrnhoefer
Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28(th) Avenue, Vancouver, BC, V5Z 4H4, Canada.
Nicholas S
NS
Caron
Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28(th) Avenue, Vancouver, BC, V5Z 4H4, Canada.
Yu
Y
Deng
Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28(th) Avenue, Vancouver, BC, V5Z 4H4, Canada.
Xiaofan
X
Qiu
Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28(th) Avenue, Vancouver, BC, V5Z 4H4, Canada.
Michelle
M
Tsang
Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, 950 West 28(th) Avenue, Vancouver, BC, V5Z 4H4, Canada. Electronic address: mrh@cmmt.ubc.ca.
Michael R
MR
Hayden
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D019556:COS Cells; D002166:Camptothecin / Q000494:pharmacology; D053178:Caspase 6 / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D013997:Time Factors; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000031:analogs & derivatives / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; C086055:HTT protein, human; D000071058:Huntingtin Protein; D011500:Protein Synthesis Inhibitors; D015363:Quinolones; D051028:bcl-2-Associated X Protein; C425776:tyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; C476223:laquinimod; D053178:Caspase 6; D002166:Camptothecin
Bax; Caspase-6; Huntington disease; Laquinimod; Neuronal apoptosis; YAC128