Glial cell lineage expression of mutant ataxin-1 and huntingtin induces developmental and late-onset neuronal pathologies in Drosophila models.
BACKGROUND
In several neurodegenerative disorders, toxic effects of glial cells on neurons are implicated. However the generality of the non-cell autonomous pathologies derived from glial cells has not been established, and the specificity among different neurodegenerative disorders remains unknown.


RESULTS
We newly generated Drosophila models expressing human mutant huntingtin (hHtt103Q) or ataxin-1 (hAtx1-82Q) in the glial cell lineage at different stages of differentiation, and analyzed their morphological and behavioral phenotypes. To express hHtt103Q and hAtx1-82Q, we used 2 different Gal4 drivers, gcm-Gal4 and repo-Gal4. Gcm-Gal4 is known to be a neuroglioblast/glioblast-specific driver whose effect is limited to development. Repo-Gal4 is known to be a pan-glial driver and the expression starts at glioblasts and continues after terminal differentiation. Gcm-Gal4-induced hHtt103Q was more toxic than repo-Gal4-induced hHtt103Q from the aspects of development, locomotive activity and survival of flies. When hAtx1-82Q was expressed by gcm- or repo-Gal4 driver, no fly became adult. Interestingly, the head and brain sizes were markedly reduced in a part of pupae expressing hAtx1-82Q under the control of gcm-Gal4, and these pupae showed extreme destruction of the brain structure. The other pupae expressing hAtx1-82Q also showed brain shrinkage and abnormal connections of neurons. These results suggested that expression of polyQ proteins in neuroglioblasts provided a remarkable effect on the developmental and adult brains, and that glial cell lineage expression of hAtx1-82Q was more toxic than that of hHtt103Q in our assays.


CONCLUSIONS
All these studies suggested that the non-cell autonomous effect of glial cells might be a common pathology shared by multiple neurodegenerative disorders. In addition, the fly models would be available for analyzing molecular pathologies and developing novel therapeutics against the non-cell autonomous polyQ pathology. In conclusion, our novel fly models have extended the non-cell autonomous pathology hypothesis as well as the developmental effect hypothesis to multiple polyQ diseases. The two pathologies might be generally shared in neurodegeneration.
Tamura
Takuya
T
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Sone
Masaki
M
Yamashita
Mayumi
M
Wanker
Erich E
EE
Okazawa
Hitoshi
H
D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D019070:Cell Lineage; D003433:Crosses, Genetic; D004331:Drosophila melanogaster; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000071058:Huntingtin Protein; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D010455:Peptides / Q000378:metabolism
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine