Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants

Abstract

The fruitfly Drosophila melanogaster has enabled significant advances in neurodegenerative disease research, notably in the identification of genes that are required to maintain the structural integrity of the brain, defined by recessive mutations that cause adult onset neurodegeneration. Here, we survey these genes in the fly and classify them according to five key cell biological processes. Over half of these genes have counterparts in mice or humans that are also associated with neurodegeneration. Fly genetics continues to be instrumental in the analysis of degenerative disease, with notable recent advances in our understanding of several inherited disorders, Parkinson's disease, and the central role of mitochondria in neuronal maintenance.

FIGURE 1. Cellular processes implicated by neurodegeneration genes

A Venn diagram showing the relationships between five cellular processes and a suggested classification of the neurodegeneration genes from SI TABLE 1, many of which have multiple roles.

FIGURE 2. Neurodegeneration proteins associated with the mitochondrion

Gene products from SI TABLE 1 are highlighted in orange. In black in the same font are proteins not in the table that genetically interact (or are predicted to interact) with the neurodegeneration proteins. At the bottom left, transport of mitochondria into neurites depends on the (+) end-directed motor Kinesin and on microtubules (pink tubule), which are stabilized by FUTSCH. The dare product transfers electrons from NADPH to adrenodoxin, which in turn transfers them to a cytochrome P450, which catalyzes the first step in steroid hormone synthesis. At left, fatty acids are activated by a number of steps before importation (black dashed arrow; see text) into the matrix for oxidation. Together with the citric acid cycle, these pathways generate the electron carriers NADH and FADH₂, which in turn power the complexes of the electron transport chain (blue, top). Proton flux across the inner membrane is indicated by dashed arrows. Incoming protons drive synthesis of ATP, which is transported out of the matrix (dashed arrow) by the ATP/ADP translocator (green). Low ATP generation results in activation of AMP-activated protein kinase (AMPK, orange). At the bottom right, PINK1 regulates TRAP1 and the localization of PARK (see text); pink1 and park interact with genes that regulate mitochondrial fission and fusion, consistent with these gene products acting downstream of PARK, as shown here, although there is no direct evidence for this yet. Pink1 also regulates another parkinsonism protein, HTRA2, and a Na⁺/Ca²⁺ antiporter activity (see text). High Ca²⁺ levels within the matrix will trigger formation of the permeability transition pore (PTP), through which cytochrome c can be released, activating caspases and apoptosis. (Not shown are apoptosis inducing factor and members of the BCL2 family, proteins that also regulate apoptosis and translocate between the cytoplasm and the outer surface of mitochondria. See ref. 72)