Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder in humans characterized by progressive degeneration of skeletal muscle and motor neurons in spinal cord, brainstem, and cerebral cortex causing skeletal muscle paralysis, respiratory insufficiency, and death. There are no cures or effective treatments for ALS. ALS can be inherited, but most cases are not associated with a family history of the disease. Mitochondria have been implicated in the pathogenesis but definitive proof of causal mechanisms is lacking. Identification of new clinically translatable disease mechanism-based molecular targets and small molecule drug candidates are needed for ALS patients. We tested the hypothesis in an animal model that drug modulation of the mitochondrial permeability transition pore (mPTP) is therapeutic in ALS. A prospective randomized placebo-controlled drug trial was done in a transgenic (tg) mouse model of ALS. We explored GNX-4728 as a therapeutic drug. GNX-4728 inhibits mPTP opening as evidenced by increased mitochondrial calcium retention capacity (CRC) both in vitro and in vivo. Chronic systemic treatment of G37R-human mutant superoxide dismutase-1 (hSOD1) tg mice with GNX-4728 resulted in major therapeutic benefits. GNX-4728 slowed disease progression and significantly improved motor function. The survival of ALS mice was increased significantly by GNX-4728 treatment as evidence by a nearly 2-fold extension of lifespan (360 days–750 days). GNX-4728 protected against motor neuron degeneration and mitochondrial degeneration, attenuated spinal cord inflammation, and preserved neuromuscular junction (NMJ) innervation in the diaphragm in ALS mice. This work demonstrates that a mPTP-acting drug has major disease-modifying efficacy in a preclinical mouse model of ALS and establishes mitochondrial calcium retention, and indirectly the mPTP, as targets for ALS drug development.
Highlights
Mitochondrial mechanisms have been implicated in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS; Wong et al, 1995; Bendotti et al, 2001; Beal, 2005; Martin, 2010a; Reddy and Reddy, 2011; Muyderman and Chen, 2014)
This study shows that chronic treatment of G37R-human mutant superoxide dismutase-1 tg mice with GNX-4728 strongly protects against onset of ALS and robustly extends survival with preservation of motor neuron number, motor neuron mitochondria, and neuromuscular junction (NMJ) integrity
Our study demonstrates that a small molecule cinnamic anilide derivative, GNX-4728, has several major therapeutic benefits in a mouse model of ALS
Summary
Mitochondrial mechanisms have been implicated in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS; Wong et al, 1995; Bendotti et al, 2001; Beal, 2005; Martin, 2010a; Reddy and Reddy, 2011; Muyderman and Chen, 2014). Mitochondrial-based mechanisms of disease in ALS might include failure of intracellular Ca2+ homeostasis, oxidative stress propagation, energy depletion, perturbed fission-fusion dynamics, and cell death initiation (Beal, 2005; Reddy and Reddy, 2011), but it is possible that mitochondrial changes are indirectly related to disease etiology and are secondary or bystander events (Morais and De Strooper, 2010; Muyderman and Chen, 2014). The mitochondrial permeability transition pore (mPTP) is emerging as a critical player in neurodegenerative disease and in acute neuropathology (Martin et al, 2009; Martin, 2010a,b)
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