During normal aging and in the progression of many neurodegenerative disorders the accumulation of cellular damage can perturb the normal function of the nervous system and change behaviors and memory. A growing body of evidence shows that the highly conserved macroautophagy pathway (autophagy) is involved in maintaining the mature nervous system by facilitating the bulk removal of cellular damage and protein aggregates. Recently we have examined the aging profiles of autophagy genes and found the pathway is significantly suppressed in the older Drosophila CNS. At the same time, cellular damage markers including insoluble ubiquitinated proteins (IUP) show a dramatic increase in older fly brains. Genetic analysis identifies mutations in key genes that also significantly shorten adult lifespans (35 to 60%) and cause progressive neural defects that share striking similarities to those seen in Alzheimer's patents. Both phenotypes are signs of accelerated aging and an inability of neurons to clear cellular damage effectively. Of greater significance is our recent observation that upregulating or enhancing the level of rate-limiting components of the pathway in the adult nervous system suppresses the normal age- dependent accumulation of cellular damage (IUP) and significantly extends adult longevity nearly 60%. Taken together both the acceleration and suppression of age-dependent phenotypes shows that modeling changes to the mature nervous system can be done effectively in Drosophila, in order to gain a greater understanding of cellular factors involved with aging and progressive neural decline. In this proposal we take advantage of the conserved function of autophagy and its regulation, and coupled this information together with Drosophila genetic and transgenic techniques to identify neural protective compounds that enhance autophagy and promote adult longevity and neural function. Studies in Aim 1 will use the GAL4/UAS system to express neural toxic peptides in photoreceptor cells or throughout the adult CNS. Compounds will be screened for their ability to reduce cytotoxic phenotypes associated with their expression in neural tissues and cells.
For Aim 2 compounds and concentration ranges identified in Aim 1 will be used to examine the ability of drugs to enhance autophagy and clear cellular damage that naturally occurs in aging adult Drosophila nervous system.
For Aim 3 once a select set of compounds are identified they will be used in long-term aging studies to test their ability to extend adult lifespans. In addition, unique drug combinations and treatment regimes can also be quickly design and rapidly tested due to the powerful genetics and compressed lifespans of Drosophila. The overall goal of this proposal is to better understand the critical role that clearance pathways play in aging and to develop a rapid in vivo method to design and test drugs that can be used for the treatment of human neurological disorders.
Alzheimer's disease and other age-related neurological disorders affect millions of people worldwide. At this time treatment options are limited and characterization of new therapeutic compounds requires the development of novel methods to systematically test drug efficacy. The research outlined in this proposal will develop rapid in vivo screening techniques in Drosophila that detect changes in neural degenerative phenotypes associated with aging and loss of neuronal damage-control pathways like autophagy.
| Bartlett, Bryan J; Isakson, Pauline; Lewerenz, Jan et al. (2011) p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects. Autophagy 7:572-83 |
