Studying the interaction of Huntingtin and HAP40: potential functional implications

• Applicant: Professor Dr. Stefan Kochanek
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412854449

• Final Report Year: 2023

Final Report Abstract

Huntington's disease (HD) is a fatal autosomal-dominant inherited neurodegenerative disorder caused by a mutation in the HTT gene. The interaction between HTT and HAP40, a protein associated with HTT, was studied to gain insight into its function and its potential contribution to HD. Analysis revealed the co-evolution of HAP40 and HTT and that the interaction is likely conserved in metazoans. Furthermore, the family of soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs) were identified as closest homologs of HAP40 and that both proteins evolved from a common fully formed ancestral tetratricopeptide repeat (TPR) protein. Suggesting a role of HAP40 in the pathophysiology of HD, HAP40 protein levels were found to depend directly on HTT levels, and the overexpression of HTT increased the stability of HAP40. Reduced levels of both proteins were observed in HD patients, highlighting the dependence of HAP40 levels on HTT levels. This strong correlation suggests that HAP40 could serve as a surrogate biomarker for measuring HTT protein levels, particularly for assessing the effectiveness of HTT-lowering therapies in HD. Our findings highlight the critical role of HAP40 as an obligate partner of HTT and emphasize the need for further investigations into its specific function. Moreover, understanding the implications of HTT-lowering therapies on HAP40 and other HTT interactors is of utmost importance. These findings contribute to advancing our knowledge of HD pathophysiology and provide insights that may aid in the development of novel diagnostic and therapeutic strategies for this devastating disease.

Publications

• The evolution of the huntingtin-associated protein 40 (HAP40) in conjunction with huntingtin. BMC Evolutionary Biology, 20(1).
  Seefelder, Manuel; Alva, Vikram; Huang, Bin; Engler, Tatjana; Baumeister, Wolfgang; Guo, Qiang; Fernández-Busnadiego, Rubén; Lupas, Andrei N. & Kochanek, Stefan
  
• A meta-analysis of transcriptomic profiles of Huntington’s disease patients. PLOS ONE, 16(6), e0253037.
  Seefelder, Manuel & Kochanek, Stefan
  
• A07 Huntingtin-dependent stability of HAP40 and decreased HAP40 levels in huntington’s disease. A: Pathogenic mechanisms, A3.1-A3. BMJ Publishing Group Ltd.
  Seefelder, Manuel; Huang, Bin; Buck, Eva; Engler, Tatjana; Lindenberg, Katrin S.; Landwehrmeyer, Bernhard & Kochanek, Stefan
  
• HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease. Neurobiology of Disease, 158, 105476.
  Huang, Bin; Seefelder, Manuel; Buck, Eva; Engler, Tatjana; Lindenberg, Katrin S.; Klein, Fabrice; Landwehrmeyer, G. Bernhard & Kochanek, Stefan
  
• Pathological polyQ expansion does not alter the conformation of the Huntingtin-HAP40 complex. Structure, 29(8), 804-809.e5.
  Huang, Bin; Guo, Qiang; Niedermeier, Marie L.; Cheng, Jingdong; Engler, Tatjana; Maurer, Melanie; Pautsch, Alexander; Baumeister, Wolfgang; Stengel, Florian; Kochanek, Stefan & Fernández-Busnadiego, Rubén
  
• Huntingtin and Its Partner Huntingtin-Associated Protein 40: Structural and Functional Considerations in Health and Disease. Journal of Huntington's Disease, 11(3), 227-242.
  Seefelder, Manuel; Klein, Fabrice A.C.; Landwehrmeyer, Bernhard; Fernández-Busnadiego, Rubén & Kochanek, Stefan