• Huntington's disease

This report describes Huntington disease (HD), an inherited neurodegenerative disease with a single causative gene; the disease is inherited as an autosomal dominant. Huntington disease was the first CAG-repeat disease for which the gene was identified and characterized molecularly. These diseases, largely neurodegenerative in nature, are caused by expansion of CAG repeats within the coding region of the causative gene, resulting in an expanded run of glutamine (Q) residues in the encoded protein. The human gene implicated in HD is HTT, a widely expressed gene for which the function is not known. There is a single high-scoring fly ortholog, Dmel\htt, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated; an amorphic genotype has been created and characterized.

UAS constructs of the human Hsap\HTT gene have been introduced into flies; heterologous rescue (functional complementation) has been demonstrated for the eye phenotype of an RNAi allele of Dmel\htt expressed in the adult eye. Hsap\HTT transgenes with CAG expansions expressed in the fly eye induce degeneration and death of adult photoreceptor neurons resulting in an easily scored and semi-quantitative phenotype, allowing detection of genetic interactions and screening of synthetic compounds.

UAS-HTT constructs with differing numbers of the pathological CAG repeat have been created; see the 'Disease-Implicated Variants' table below. Pan-neuronal expression of pathological expansions results in progressive locomotor defects and neuroanatomy defects, including progressive degeneration of photoreceptor rhabdomeres in the eye. Expression in the developing eye only has been used to assess development of neuroanatomy defects.

Cardiomyopathy is observed at elevated rates among HD patients; uncontrolled weight loss is also frequently associated with the disease. These aspects of the disease have been investigated in flies. Cardiac-specific expression of pathogenic Hsap\HTT polyQ constructs has allowed cellular and molecular characterization of the resulting cardiac dysfunction. Hsap\HTT transgenes with CAG expansions expressed in the fat body result in weight loss in flies, despite higher food intake, and eventual death. In a study associating metabolic phenotypes with variants found in the Drosophila Genetic Reference Panel (DGRP) lines, Dmel\htt emerged as having a significant metabolic role. Assessment of htt knockdown flies revealed dramatic increases in body size and starvation resistance. These results in flies appear to support a mechanism involving a toxic gain-of-function in the mutant protein rather than a loss of wild-type HTT function for the uncontrolled weight loss associated with Huntington disease.

Using pan-neuronal expression of an Hsap\HTT transgene with CAG expansion, it has been shown that transposable element expression and mobilization are increased in larval and adult brains. Evidence of genomic instability is observed. Reverse transcriptase inhibitors (administered by feeding) suppress the HD eye phenotypes and HD-induced genome instability. See also the Human Disease Model report 'tauopathies, heterochromatin decondensation and transposable element dysregulation' (FBhh0001010).

Animals with a null genotype for htt appear to develop normally into adulthood; as they age, they exhibit a progressive decline in mobility; they also have a shortened adult lifespan. (See above for loss-of-function metabolic phenotypes.)

Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).

[updated Feb. 2022 by FlyBase; FBrf0222196]