Figure 5.

Model of mitochondrial dysfunction in ALS and proposed interventions. Expression of TDP^WT or TDP^G298S in motor neurons causes alterations in the expression of carnitine shuttle components (ALS mitochondria, B) compared to controls (Healthy mitochondria, A). Blue dashed line for CPT1 indicates an upward trend in transcript levels (P_value = 0.08). These defects can be countered genetically, by reducing CPT1 in the context of TDP^WT (inhibitory blue symbol), or reducing CPT2 in the context of TDP^G298S (inhibitory magenta symbol). Magenta asterisk indicates a potential compensatory mechanism whereby CPT1 RNAi knock-down mitigates TDP^G298S locomotor phenotypes despite CPT1 mRNA being reduced. Alternatively, dietary supplementation with medium-chain fatty acids or beta-hydroxybutyrate bypasses carnitine shuttle dysfunction leading to significant improvement in locomotor function (C, Lipid metabolism interventions in ALS).