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Vesicular glutamate transporter modulates sex differences in dopamine neuron vulnerability to age‐related neurodegeneration.
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- Author(s): Buck, Silas A.1,2 (AUTHOR); Steinkellner, Thomas3,4 (AUTHOR); Aslanoglou, Despoina2 (AUTHOR); Villeneuve, Michael2 (AUTHOR); Bhatte, Sai H.2 (AUTHOR); Childers, Victoria C.2 (AUTHOR); Rubin, Sophie A.2 (AUTHOR); De Miranda, Briana R.5 (AUTHOR); O'Leary, Emma I.1 (AUTHOR); Neureiter, Elizabeth G.1,2 (AUTHOR); Fogle, Keri J.6,7 (AUTHOR); Palladino, Michael J.6,7 (AUTHOR); Logan, Ryan W.8,9 (AUTHOR); Glausier, Jill R.2 (AUTHOR); Fish, Kenneth N.2 (AUTHOR); Lewis, David A.2 (AUTHOR); Greenamyre, J. Timothy5,7,10 (AUTHOR); McCabe, Brian D.11 (AUTHOR); Cheetham, Claire E. J.12 (AUTHOR); Hnasko, Thomas S.3,13 (AUTHOR)
- Source:
Aging Cell. May2021, Vol. 20 Issue 5, p1-14. 14p.- Subject Terms:
- Source:
- Additional Information
- Abstract: Age is the greatest risk factor for Parkinson's disease (PD) which causes progressive loss of dopamine (DA) neurons, with males at greater risk than females. Intriguingly, some DA neurons are more resilient to degeneration than others. Increasing evidence suggests that vesicular glutamate transporter (VGLUT) expression in DA neurons plays a role in this selective vulnerability. We investigated the role of DA neuron VGLUT in sex‐ and age‐related differences in DA neuron vulnerability using the genetically tractable Drosophila model. We found sex differences in age‐related DA neurodegeneration and its associated locomotor behavior, where males exhibit significantly greater decreases in both DA neuron number and locomotion during aging compared with females. We discovered that dynamic changes in DA neuron VGLUT expression mediate these age‐ and sex‐related differences, as a potential compensatory mechanism for diminished DA neurotransmission during aging. Importantly, female Drosophila possess higher levels of VGLUT expression in DA neurons compared with males, and this finding is conserved across flies, rodents, and humans. Moreover, we showed that diminishing VGLUT expression in DA neurons eliminates females' greater resilience to DA neuron loss across aging. This offers a new mechanism for sex differences in selective DA neuron vulnerability to age‐related DA neurodegeneration. Finally, in mice, we showed that the ability of DA neurons to achieve optimal control over VGLUT expression is essential for DA neuron survival. These findings lay the groundwork for the manipulation of DA neuron VGLUT expression as a novel therapeutic strategy to boost DA neuron resilience to age‐ and PD‐related neurodegeneration. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of Aging Cell is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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