• neurodegenerative disease

It has been shown that Drosophila Mitf gene plays a role analogous to that of the orthologous human genes, transcription factors of the MiTF-TFE family, in regulation of the lysosomal-autophagy pathway. The MiTF-TFE family, also called the microphthalmia family, consists of 4 genes in human: MITF, TFEB, TFE3, and TFEC. Dmel\Mitf is the single member of this family in Drosophila. Loss-of-function alleles and RNAi targeting constructs have been generated for Dmel\Mitf.

UAS constructs of the wild-type human Hsap\MITF and Hsap\TFEB genes have been introduced into flies, but have not been characterized. The other human genes in this family (TFE3, TFEC) have not been introduced into flies.

Reduction of Mitf function via RNAi leads to abnormal lysosomes; impaired autophagosome fusion and lipid breakdown during response to starvation are observed. In the brain of adult flies in which Mitf has been silenced using neuronal drivers, a slight but significant accumulation of polyubiquitinated protein aggregates upon starvation is observed; a slight but significant accumulation of autophagosomes is also observed.

The role of the lysosomal-autophagy pathway in the response to neurodegenerative disease associated with intracellular protein aggregation has been investigated using the fly Mitf gene introduced into a human disease model system. A human cell line model of spinocerebellar ataxia type 1 (SCA1) was used; the causative agent in SCA1 is a variant of the human ATXN1 gene with an expanded polyglutamine repeat. Transfection of Drosophila Mitf resulted in a significant drop in the number of cells with aggregates of the pathogenic ATXN1 protein in both the cytosol and the nucleus.

[updated Apr. 2020 by FlyBase; FBrf0222196]