Aloisia Schmid, Ph.D.
Assistant Professor of Human Genetics

Contribution to Society

Amyloidgenic diseases are diverse and include Alzheimer’s Disease, Parkinson’s Disease, Lou Gehrig’s Disease (ALS), Huntington’s Disease, amyloidosis, kidney diseases and a number of others. These diseases are related to the deposition of peptides that on first glance appear unrelated to one another, but on closer inspection appear to share structural homology: they contain extensive amounts of beta sheet structure, are stainable with Congo Red and other dyes, and produce fibrils that derive from pre-fibrillar soluble conformational states. It is not clear whether an as yet, unidentified insult damages and kills cells containing these proteins, leaving insoluble amyloid protein plaques behind, or whether these amyloid proteins are themselves the cuplrits in disease pathogenesis.

In considering the costs of these diseases, one considers time lost from work (for patients and care-givers), required medical care including pharmaceuticals and hospitalization, and indirect costs, such as those related to accidents attributed to dementia. Conservative estimates place these costs at more than one trillion dollars per year and do not factor in the emotional traumas associated with these diseases.

We are using invertebrate genetics to model human diseases; our hope is to identify molecular targets for future therapeutics, and to identify the genes responsible for sensitivity or resistance to the insults that lead to these diseases.

Research Summary

Drosophila genetics have traditionally been used to dissect embryonic development, cell biology, physiology and even behavior, but their use in unraveling the pathologies of human disease is new. Work in other labs has shown that flies misexpressing human amyloidgenic peptides generate animal models of human disease that are considered the best thus far developed: they exhibit an age-related neurodegeneration, specific neuronal losses, and (screenable) behavioral phenotypes that mimic those observed in human patients and can be investigated in genetic screens. Flies respond to the same drug treatments that human patients respond to, in the same dosage and efficacy ranges, suggesting that the cell biology of these pathologies is conserved. I am able to examine the effects of mutations in known human disease genes on the embryonic fly central nervous system (CNS) at the single cell level, providing an understanding of how these mutations affect neurons in a way that cannot be achieved by more conventional approaches in invertebrates and vertebrates.

My long term goal is to investigate the mechanisms that kill specific subsets of neurons in neurodegeneration diseases, focusing on why these cells die in these diseases and the cellular basis of amyloid toxicity. The neuronal defects associated with misexpressing human amyloidgenic peptides in specific cells of the CNS, studied at the single cell level, allow us to examine the role of cell biology in these disease states. Currently, we are designing models of Spinal Muscular Atrophy (SMA) (see figure below), Alzheimer’s Diseases and Depression. I have also designed a high throughput drug screen that we are developing for use with these Drosophila models of human disease.

Many neurodegenerative diseases are associated with epigenetic risk factors as well. Ten percent of Parkinson's Disease patients suffer from a genetic mutation that produces the disease, but the remaining 90% develop PD from unidentified (idiopathic) insults. Farm workers are known to develop the disease at a significantly higher rate than do their urban counterparts---and the chemicals used routinely as pesticides have proved useful in rodent models to generate parkinsonian deficits. We have been conducting a careful comparison in the fly, of the various chemical paradigms for PD, including rotenone, MPTP (or rather, its metabolite, MPP+), paraquat, 6-hydroxydopamine. We have been successful at generating flies that have Parkinsonian behaviors that can be used in genetic screens. These include rigidity, an inability to initiate movement, and a distinct tremor. Students in my lab are performing a careful correlation of unique and sensitive behavioral assays with an adult-onset, dopaminergic neuronal loss. My goal is to identify genes that will ultimately reveal more of the cell biology of neurodegeneration in Parkinson’s Disease; we hope to identify what makes dopaminergic neurons susceptible to chemical insults, and what confers resistance to them.

This work will provide an excellent starting point for the initiation of modifier screens that will identify the genes involved in a generic cellular neurodegenerative pathway.

Recent Publications

1. Schmid A, Schindelholz B, Zinn, K (2002) Combinatorial RNAi: a method for evaluating the functions of gene families in Drosophila. TINS, In Press

2. Sun Q, Schindelholz B, Knirr M, Schmid A, Zinn K (2001) Complex genetic interactions among four receptor tyrosine phosphatases regulate axon guidance in Drosophila. Molectular and Cellular Neuroscience 17:274-291

3. Sun Q, Bahri S, Schmid A, Chia W, Zinn K (2000) Receptor tyrosine phosphatases regulate axon guidance across the midline of the Drosophila embryo. Development 127(5):801-812

4. Zinn K, Schmid A (1999) Derailed axons get on track. Nature 402(6761):475-6

5. Schmid A, Chiba A, Doe CQ (1999) Clonal analysis of Drosophila embryonic neuroblasts: neural cell types, axon projections and muscle targets. Development 126(21):4654-4689 .