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Review
. 2024 May 31;14(6):320.
doi: 10.3390/metabo14060320.

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases

Alisha Vohra  1 , Patrick Keefe  1 , Prasanth Puthanveetil  2
Affiliations
Review

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases

Alisha Vohra et al. Metabolites. .

Abstract

Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is not well studied and needs more attention. We have brought to light the significance of regulating glutamine metabolism during polyglutamine diseases, which could help in decreasing the neuronal damage associated with excess glutamate and nucleotide generation. Most polyglutamine diseases are accompanied by symptoms that occur due to excess glutamate and nucleotide accumulation. Along with a dysregulated glutamine metabolism, the Nicotinamide adenine dinucleotide (NAD+) levels drop down, and, under these conditions, NAD+ supplementation is the only achievable strategy. NAD+ is a major co-factor in the glutamine metabolic pathway, and it helps in maintaining neuronal homeostasis. Thus, strategies to decrease excess glutamate and nucleotide generation, as well as channelizing glutamine toward the generation of ATP and the maintenance of NAD+ homeostasis, could aid in neuronal health. Along with understanding the metabolic dysregulation that occurs during polyglutamine diseases, we have also focused on potential therapeutic strategies that could provide direct benefits or could restore metabolic homeostasis. Our review will shed light into unique metabolic causes and into ideal therapeutic strategies for treating complications associated with polyglutamine diseases.

Keywords: NAD+ regulation; metabolic signaling; neuronal health; polyglutamine diseases; therapeutics.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Altered NAD+ regulation during polyglutamine diseases. Tryptophan metabolism is responsible for the generation of NAD+. Kynurenine needs to undergo further metabolism to generate quinolinic acid with a subsequent generation of NAD+. During polyglutamine disease, the tryptophan metabolism could be altered, leading to an enhanced kynurenic acid generation and decreased formation of quinolinic acid with a resultant decrease in NAD+ generation.
Figure 2
Figure 2
A distorted glutamine–glutamate cycle during polyglutamine diseases. A balance in the glutamine–glutamate cycle is very important for neuronal homeostasis. During polyglutamine diseases, this homeostasis is altered, resulting in either enhanced glutamate, reduced glutathione formation, or both.
See this image and copyright information in PMC

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Grants and funding

P.P. received funding support from Midwestern University through New Faculty Startup Funds. A.V. and P.K. were supported by the Federal Work Study program at Midwestern University.

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