Mitochondria: de gemeenschappelijke oorzaak in ALS?

Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease resulting in the loss of upper and lower motor neurons, responsible for muscle movement, in the motor cortex, brain and spinal cord. Patients suffering from ALS will experience progressive muscle weakness and paralysis and will eventually die, most often due to respiratory failure. Although decades of ground-breaking research lay behind us, it appears as if we are still no closer to identifying the underlying disease pathology causing the specific degeneration of motor neurons or towards discovering an effective cure for ALS patients. Nevertheless, there is ample evidence to believe that the large range of disease origins eventually converge and cause motor neuron degeneration through one or multiple common mechanisms. Identification of the(se) common denominator(s) is crucial and will form the basis for future effective drug development and treatment of patients. Throughout years of ALS research, mitochondrial dysfunction has been a consistent and ever-returning observation. As a consequence, mitochondrial dysfunction has been hypothesised to be the common denominator causing ALS-related neurodegeneration. Therefore, at the start of this PhD project, we set out on a quest to identify whether mitochondrial defects might indeed be the answer to our questions and whether mitochondrial dysfunction is a common denominator in ALS. During this PhD, we explored the impact of the disease-causing SOD1G93A/wt, VCPR191Q/wt and TBK1R357*/wt mutations on mitochondrial function using CRISPR/Cas9-engineered neuroblastoma cell lines. Additionally, we aimed to investigate whether a common pathological mechanism could be identified across all three conditions. We found that mitochondria in all three ALS mutant cell lines have a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Moreover, the observation of mitochondrial depolarization could, at least partially, be confirmed in induced pluripotent stem cell (iPSC)-derived motor neurons carrying ALS-causing mutations in the SOD1 and VCP genes. Our results indicate that mitochondrial hypermetabolism is caused by increased opening of the mitochondrial permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. Furthermore, we found evidence suggesting that the observed mPTP opening is caused by mitochondrial matrix calcium overload, especially in the mutant VCP cell line. In conclusion, our findings reveal a central role of the ALS genes SOD1, VCP and TBK1 in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics underlying ALS-associated motor neuron degeneration.