Approaches

Drosophila: fast and in vivo

Chart compares fast versus in vivo system models Model systems comparison

Implementing a combination of model systems ensures quickness, in vivo testing and patient relevance

Using Drosophila as a model system has several advantages. First, the generation time of Drosophila is only about two weeks, allowing for complicated genetic manipulation. Secondly, it is relatively inexpensive and easy to handle, allowing for large-scale genetic screens. In addition, 70 percent of fly genes are conserved in humans, which makes translating mechanistic studies in Drosophila to humans possible.

To study neurodegeneration in Drosophila, a commonly used phenotypic readout is the external morphology of the eye. The Drosophila compound eye consists of around 800 single eyes (ommatidia), which are organized in a hexagonal pattern. Each ommatidium contains eight photoreceptor neurons, which are surrounded by glia. Using this system, one can easily screen genetic modifiers or drugs that modulate eye degeneration. In addition to the visual system, the Drosophila motor system is widely used to study synaptic functions and behavior.

Limitations

Compared with mammals, Drosophila is less relevant to humans. In addition, many cell biology tools (antibodies, for example) are lacking in Drosophila, which makes cell biology studies sometimes difficult.

Further readings

Human immortalized cell lines: fast and human relevant

Another model system used in the Zhang lab is human immortalized cell lines. Given their ease of handling, they are an ideal system for the study of molecular and cellular mechanisms of diseases. Furthermore, they are good systems for the study of fundamental questions in cell biology.

Limitations

Cultured cells are in vitro. Also, these cells are not nerve cells.

Patient iPSC-derived neurons: best patient-relevance

In past decades, translating discoveries in rodent models to patients with neurodegenerative diseases has been only rarely successful. Thus, a more human-relevant model system is needed. The iPSC-derived neurons come from patient cells, providing direct relevance to humans. We use iPSC-derived neurons to verify our findings in Drosophila and cell line studies.

Limitations

iPSC experiments are expensive and labor-intensive. Also, they are not in vivo.

Mice: in vivo and mammalian

Before translating our studies to clinics, it is critical to fully assess their effects in live mammals. As such, we use mouse models to verify our findings from studies in Drosophila, cell lines and iPSC-derived neurons.

Limitations

Mouse experiments are labor-intensive and time-consuming. Also, mice are not humans. Currently, the Zhang lab only does limited mouse experiments. For most of our mouse work, we collaborate with Leonard Petrucelli, Ph.D., and Yongjie Zhang, Ph.D., who have generated several C9orf72-mediated amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS-FTD) mouse models.