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

Suvithanandhini Loganathan,Sara B Carey,Bryce A Wilson,Daniela C Zarnescu,Ernesto Manzo,Archi Joardar,Berrak Ugur

doi:10.3390/metabo12020101

Suvithanandhini Loganathan, Sara B Carey + Show 5 more

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https://doi.org/10.3390/metabo12020101

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Journal: Metabolites	Publication Date: Jan 21, 2022
Citations: 7	License type: CC BY 4.0

Affiliation: University of Arizona, Yale University

Abstract

Amyotrophic lateral sclerosis (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 Tricarboxylic acid (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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects both upper and lower motor neurons (MNs)
To study global metabolic alterations in ALS, we used Drosophila models of TDP-43 proteinopathy based on overexpression of wildtype TDP-43 (TDP-43WT ) or an ALS-associated mutant variant, G298S (TDP-43G298S ), in motor neurons
Our model has previously identified metabolic and molecular alterations that were subsequently validated in ALS spinal cords and induced pluripotent stem cell-derived MNs [13,18,19]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects both upper and lower motor neurons (MNs). Several clinical studies have reported that ALS patients exhibit hypermetabolism, altered energy and lipid metabolism, weight loss, dyslipidemia, insulin resistance, and altered glucose tolerance, as reviewed in [3,4] Metabolic interventions such as high calorie diets and metabolic supplements have been shown to delay disease progression in animal models, as reviewed in [4]. It remains unclear how these metabolic changes contribute to disease progression or selective degeneration of MNs. In addition, high body mass index and diabetes have been associated with increased survival in ALS patients [5].

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