A three-molecule complex emerges as a potential target for treating Huntington’s disease
An international research team, including scientists from the German Center for Neurodegenerative Diseases (DZNE) in Bonn and the University of Mainz, has identified a molecular complex that regulates production of the toxic form of the Huntingtin protein. The results, published in the journal Nature Communications, show that the MID1 protein complex binds to mutant HTT mRNA and increases synthesis of the disease-causing protein, suggesting a promising new avenue for therapy.
Huntington’s disease (HD), also called Huntington’s chorea, is an inherited neurodegenerative disorder characterized by progressive movement disorders, cognitive decline, and psychiatric symptoms. In Germany, roughly 8,000 people live with HD, and several hundred new symptomatic cases appear annually. Symptoms typically onset between ages 35 and 50, and the disease is currently incurable. HD is caused by an expansion of CAG trinucleotide repeats in the HTT gene; unusually long repeats result in an extended polyglutamine tract in the Huntingtin protein, disrupting its normal function and making it toxic to neurons.
Focus on protein synthesis: translation of HTT mRNA
The research team, led by Dr. Sybille Krauss and geneticist Susann Schweiger, focused on translation, the step where ribosomes read messenger RNA (mRNA) to build proteins. In HD patients, HTT mRNA carries an abnormal number of consecutive CAG codons, each encoding the amino acid glutamine. These expanded repeats cause over-incorporation of glutamine into the Huntingtin protein, producing a mutant form that damages nerve cells.
Using biochemical methods, cell culture models, and brain tissue from genetically modified mice bearing elongated CAG repeats, the investigators discovered that a complex of three proteins—MID1, PP2Ac, and S6K—selectively binds to HTT mRNA containing long CAG tracts. Binding strength increased with repeat length, while normal-length HTT mRNA showed little or no interaction. MID1 appears to be the central scaffold that recruits PP2Ac and S6K to the expanded CAG repeat sequences.
MID1 complex enhances mutant Huntingtin production
Functional experiments demonstrated that the MID1 complex actively promotes translation of HTT mRNA with expanded CAG repeats. When researchers reduced MID1 levels in cells using knockdown approaches, translation of mutant Huntingtin decreased significantly, while production of normal Huntingtin remained largely unaffected. These results indicate that the MID1–PP2A–S6K complex specifically targets pathogenic HTT mRNA and increases synthesis of the toxic protein.
The specificity is particularly important for therapeutic development: suppressing only the mutant protein while preserving normal Huntingtin could avoid impairing the essential roles of the wild-type protein. Huntingtin is a multifunctional protein required for cellular processes and organismal survival, so selective inhibition of mutant HTT synthesis is a desirable strategy.
Therapeutic implications and next steps
Targeting the MID1 complex represents a novel therapeutic approach for Huntington’s disease. If small molecules or other interventions can be developed to disrupt MID1 binding to expanded HTT mRNA or to destabilize the complex, they might reduce production of the mutant protein at its source rather than merely treating symptoms. The research team reports plans to screen and test candidate compounds in laboratory models to identify agents that can modulate MID1 activity safely and effectively.
The study required several years of multidisciplinary work, combining molecular biology, biochemistry, cell biology, and animal models to validate the role of the MID1 complex in regulating translation of expanded CAG repeat mRNA.
Notes and references
Contact: Dr. Sybille Krauß, German Center for Neurodegenerative Diseases (DZNE), Bonn
Source: Press release from the Helmholtz Association of German Research Centres
Image credit: Nadine Griesche (adapted from the original press materials)
Original research: Krauss S, Griesche N, Jastrzebska E, Chen C, Rutschow D, Achmüller C, Dorn S, Boesch SM, Lalowski M, Wanker E, Schneider R, Schweiger S. “Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex.” Nature Communications. Published online February 26, 2013. doi: 10.1038/ncomms2514