Generation of human neuro- and muscle -degenerative disease models with Drosophila: Parkinson's disease and inclusion body myositis
Patients with Parkinson’s disease (PD) lose their motor controls resulting form the selective loss of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc) and have the ubiquitin-positive cytoplasmic protein aggregation, Lewy Body (LB), in the surviving DA neurons. The studies with Parkin, an E3 ubiquitin ligase, suggest that Parkin is important in DA neuron survival and that a functionally overlapping protein(s) with Parkin, whose expression is absent in a SNpc region, protects DA neurons in brain except for those in midbrain. One candidate is Ariadne whose human homologue (HHARI) shares its binding partners with Parkin, and is heterogeneously expressed in the midbrain.
Our data suggested that HHARI was able to interact with proteins Parkin interacts with including α-synuclein, a toxic substrate for Parkin, and that ectopic expression of human Parkin and HHARI partially rescued the muscle defects of Parkin null flies. In order to study pathological significance of their overlapping functions, we tried to use a human α-synuclein expressing Drosophila model for PD. Unfortunately, our analysis revealed that α-synuclein expression itself did not cause loss of DA neurons in the transgenic flies and neither increased sensitivity against environmental toxins such as rotenone. The contradictory findings may result from variation in methodology. Due to these problems in the animal model, we could not answer our question.
In order to study protein aggregation-related diseases, we generated a new Drosophila model for a human degenerative disease, sporadic inclusion body myositis (s-IBM) disease. The patients suffer from severe muscle weakness. Many studies suggest that intracellular accumulation of human amyloid precursor protein (APP) and its proteolytic fragments, Aβs, is sufficient for s-IBM pathogenesis. In order to understand the molecular mechanism of IBM, we drove muscle specific expression of human APP in Drosophila. The APP expressing flies showed age-dependent behavioral defects resulting from muscle degeneration and abnormal mitochondria at early stages. Interestingly, the behavioral defects were affected by not only APP expression but also culturing conditions. These findings suggest that APP expression in flies’ muscle leads to increased sensitivity to environmental factors as well as muscle weakness.