Abstract
SummaryThe neuromuscular junction (NMJ) is responsible for transforming nervous system signals into motor behavior and locomotion. In the fruit fly Drosophila melanogaster, an age‐dependent decline in motor function occurs, analogous to the decline experienced in mice, humans, and other mammals. The molecular and cellular underpinnings of this decline are still poorly understood. By specifically profiling the transcriptome of Drosophila motor neurons across age using custom microarrays, we found that the expression of the matrix metalloproteinase 1 (dMMP1) gene reproducibly increased in motor neurons in an age‐dependent manner. Modulation of physiological aging also altered the rate of dMMP1 expression, validating dMMP1 expression as a bona fide aging biomarker for motor neurons. Temporally controlled overexpression of dMMP1 specifically in motor neurons was sufficient to induce deficits in climbing behavior and cause a decrease in neurotransmitter release at neuromuscular synapses. These deficits were reversible if the dMMP1 expression was shut off again immediately after the onset of motor dysfunction. Additionally, repression of dMMP1 enzymatic activity via overexpression of a tissue inhibitor of metalloproteinases delayed the onset of age‐dependent motor dysfunction. MMPs are required for proper tissue architecture during development. Our results support the idea that matrix metalloproteinase 1 is acting as a downstream effector of antagonistic pleiotropy in motor neurons and is necessary for proper development, but deleterious when reactivated at an advanced age.
Highlights
The aging of the nervous system is manifested in the decline of cognition and memory, and in the progressive decline of motor coordination and muscle function (Doherty, 2003)
In order to elucidate the molecular events that comprise neuronal aging and allow neurodegenerative disorders to manifest, we developed a motor neuron (MN)-specific pipeline in Drosophila melanogaster to investigate the effect of the aging process on the MN transcriptome
We find that dMMP1 expression correlates with declines in motor function and overexpression of dMMP1 in young MNs mimics the effects of age on motor function
Summary
The aging of the nervous system is manifested in the decline of cognition and memory, and in the progressive decline of motor coordination and muscle function (Doherty, 2003). In order to elucidate the molecular events that comprise neuronal aging and allow neurodegenerative disorders to manifest, we developed a MN-specific pipeline in Drosophila melanogaster to investigate the effect of the aging process on the MN transcriptome. Unlike central neurons, which may alter their gene expression in response to changing environmental circumstances, MNs have a predominantly unchanging function. We predicted this would increase the signal-to-noise ratio for transcriptomics across age. Manipulations that alter the rate of aging result in altered rates of dMMP1 accumulation These data provide evidence that dMMP1 is a biomarker of aging in Drosophila motor neurons that contributes to age-dependent motor declines
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