Vesicular glutamate transporter modulates sex differences in dopamine neuron vulnerability to age-related neurodegeneration.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE

Publication: Oxford, UK : Wiley-Blackwell
Original Publication: Oxford, UK : Blackwell Pub., c2002-

Sex Characteristics*; Aging/*physiology ; Dopaminergic Neurons/*physiology ; Drosophila Proteins/*physiology ; Vesicular Glutamate Transport Proteins/*physiology; Animals ; Cell Survival ; Dopaminergic Neurons/metabolism ; Drosophila/metabolism ; Drosophila/physiology ; Drosophila Proteins/metabolism ; Female ; Humans ; Locomotion ; Male ; Mice ; Rats ; Vesicular Glutamate Transport Proteins/metabolism

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.
(© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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K99 AG059834 United States AG NIA NIH HHS; K99 ES029986 United States ES NIEHS NIH HHS; R21 AG068607 United States AG NIA NIH HHS; T32 GM008208 United States GM NIGMS NIH HHS; K08 DA031241 United States DA NIDA NIH HHS; R00 ES029986 United States ES NIEHS NIH HHS; T32 NS007433 United States NS NINDS NIH HHS; R01 DA036612 United States DA NIDA NIH HHS; R21 NS087496 United States NS NINDS NIH HHS

Keywords: Drosophila; aging; dopamine; neurodegeneration; vesicular glutamate transporter

0 (Drosophila Proteins)
0 (VGlut protein, Drosophila)
0 (Vesicular Glutamate Transport Proteins)

Date Created: 20210428 Date Completed: 20211215 Latest Revision: 20221229

20240104

PMC8135008

10.1111/acel.13365

33909313