TDP-43 Proteinopathy Causes Broad Metabolic Alterations including TCA Cycle Intermediates and Dopamine Levels in Drosophila Models of ALS

Abstract

ALS is a fatal, complex neurodegenerative disorder that causes selective degeneration of motor neurons. ALS patients exhibit symptoms consistent with altered cellular energetics such as hypermetabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance. Although evidence supports metabolic changes in ALS patients, metabolic alterations at a cellular level remain poorly understood. Here, we used a Drosophila model of ALS based on TDP-43 expression in motor neurons that recapitulates hallmark features of motor neuron disease including TDP-43 aggregation, locomotor dysfunction, and reduced lifespan. To gain insights into metabolic changes caused by TDP-43, we performed global metabolomic profiling in larvae expressing TDP-43 (WT or ALS associated mutant variant, G298S) and identified significant alterations in several metabolic pathways. Here, we report alterations in multiple metabolic pathways and highlight upregulation of TCA cycle metabolites and defects in neurotransmitter levels. We also show that modulating TCA cycle flux either genetically or by dietary intervention mitigates TDP-43-dependent locomotor defects. In addition, dopamine levels are significantly reduced in the context of TDP-43G298S, and we find that treatment with pramipexole, a dopamine agonist, improves locomotor function in vivo in Drosophila models of TDP-43 proteinopathy.

A nerve-wracking buzz: lessons from Drosophila models of peripheral neuropathy and axon degeneration

“…However, this compound does not protect against all genetic causes of ALS and its mechanism is still unclear. Metabolomic profiling of larvae with TDP-43 over-expression has also revealed a role for the Tricarboxylic acid (TCA) cycle in the pathology of ALS ( Loganathan et al, 2022 ).…”

Altered Metabolism in Motor Neuron Diseases: Mechanism and Potential Therapeutic Target

“…They continued to expand their research downstream of glycolysis to determine if altering metabolism at any state could be beneficial. Utilizing the same Drosophila model, they determined that increasing the TCA cycle by either genetic modulation or through dietary mechanisms could also eliminate locomotive deficits in this model [93]. Although other in vivo models have been created to further study ALS, minimal studies have emphasized the importance of metabolic malfunction, which should be emphasized moving forward to determine genetic differences in metabolic malfunction in ALS.…”

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“…In this sense, significant alterations were found in several metabolic pathways in TDP-43G298S mutant mice, such as the positive regulation of the metabolites of the tricarboxylic acid cycle, and defects in the levels of neurotransmitters, such as dopamine (DA). As a matter of fact, an increase in DA is related, in turn, not only to improvements in the locomotor function in vivo in the ALS Drosophila model for a TDP-43 proteinopathy [ 43 ], but also to a better cognitive status in ALS patients, given the significant decrease in the DA receptors in some areas outside the striatum [ 44 ].…”