Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila

TL;DR

This study explores how Bcl-2 proteins in fruit flies can counteract mitochondrial issues linked to aging and neurodegenerative diseases.

Contribution

The study introduces new Drosophila models for neurodegenerative diseases by manipulating Drp1 and Bcl-2 genes.

Findings

Knockdown of Drp1 impairs locomotor function but does not affect lifespan in Drosophila.

Buffy suppresses Drp1-related locomotor deficits and rescues age-related decline.

Altering Drp1 expression phenocopies neurodegenerative disease traits, which can be rescued by Buffy or Debcl manipulation.

Abstract

The relationship of Amyotrophic Lateral Sclerosis, Parkinson’s disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.

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