Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using Drosophila models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders.

Practically the entire progress in genetic and molecular elucidation of hearing mechanisms in the fruitfly, Drosophila melanogaster has occurred in the last decade. The Johnston's organ (JO), located in the fly's antenna, formally has been confirmed as the major auditory organ and mutations in many genes required for hearing have been identified using a variety of approaches. These include mutagenesis screens, gene expression patterns and other candidate gene approaches including homology to known human hereditary hearing loss genesalmost all of which have been identified over the same time period. Thus, Drosophila hearing research has metamorphosed into an exciting research field that ties together intricate physiological and mechanical mechanisms with complex developmental biology. Several reviews have summarized aspects of this progress (Eberl, 1999, Caldwell and Eberl, 2002, Jarman, 2002, Robert and Göpfert, 2002, Todi et al., 2004, Boekhoff-Falk, 2005). In this paper, we first focus on advances that reinforce the emerging conclusion that the JO is much more than a mere recapitulation of the canonical larval chordotonal sense organ type. Instead, the Drosophila JO represents an evolution to a highly specialized organ for hearing, clearly chordotonal in nature, but with some features as different from ancestral proprioceptors as the butterfly is from the caterpillar. Second, we highlight some important questions raised by these considerations, the answers to which will represent significant advances in the decade(s) to come.

Development of a functional auditory system in Drosophila requires specification and differentiation of the chordotonal sensilla of Johnston's organ (JO) in the antenna, correct axonal targeting to the antennal mechanosensory and motor center in the brain, and synaptic connections to neurons in the downstream circuit. Chordotonal development in JO is functionally complicated by structural, molecular, and functional diversity that is not yet fully understood, and construction of the auditory neural circuitry is only beginning to unfold. Here, we describe our current understanding of developmental and molecular mechanisms that generate the exquisite functions of the Drosophila auditory system, emphasizing recent progress and highlighting important new questions arising from research on this remarkable sensory system. WIREs Dev Biol 2014, 3:179–191. doi: 10.1002/wdev.128This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Nervous System Development > Flies

Mutations in SALL1 , the human homolog of the Drosophila spalt gene, result in Townes-Brocks' syndrome, which is characterized by hand/foot, anogenital, renal, and ear anomalies, including sensorineural deafness. spalt genes encode zinc finger transcription factors that are found in animals as diverse as worms, insects, and vertebrates. Here, we examine the effect of losing both of the spalt genes, spalt and spalt-related , in the fruit fly Drosophila melanogaster , and report defects similar to those in humans with Townes-Brocks' syndrome. Loss of both spalt and spalt-related function in flies yields morphological defects in the testes, genitalia, and the antenna. Furthermore, spalt / spalt-related mutant antennae show severe reductions in Johnston's organ, the major auditory organ in Drosophila . Electrophysiological analyses confirm that spalt / spalt-related mutant flies are deaf. These commonalities suggest that there is functional conservation for spalt genes between vertebrates and insects.

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s currently affect ∼25 million people worldwide. The global incidence of traumatic brain injury (TBI) is estimated at ∼70 million/year. Both neurodegenerative diseases and TBI remain without effective treatments. We are utilizing adult Drosophila melanogaster to investigate the mechanisms of brain regeneration with the long-term goal of identifying targets for neural regenerative therapies. We specifically focused on neurogenesis, i.e., the generation of new cells, as opposed to the regrowth of specific subcellular structures such as axons. Like mammals, Drosophila have few proliferating cells in the adult brain. Nonetheless, within 24 hours of a penetrating traumatic brain injury (PTBI) to the central brain, there is a significant increase in the number of proliferating cells. We subsequently detect both new glia and new neurons and the formation of new axon tracts that target appropriate brain regions. Glial cells divide rapidly upon injury to give rise to new glial cells. Other cells near the injury site upregulate neural progenitor genes including asense and deadpan and later give rise to the new neurons. Locomotor abnormalities observed after PTBI are reversed within 2 weeks of injury, supporting the idea that there is functional recovery. Together, these data indicate that adult Drosophila brains are capable of neuronal repair. We anticipate that this paradigm will facilitate the dissection of the mechanisms of neural regeneration and that these processes will be relevant to human brain repair.