Article Text

Download PDFPDF
A39 Triad of neuronal vulnerability in huntington’s disease: huntingtin proteostasis, inclusion body formation and mitochondrial function
  1. Tânia R Soares1,2,
  2. Brígida R Pinho1,
  3. Michael R Duchen2,
  4. Jorge MA Oliveira1
  1. 1REQUIMTE/LAQV, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
  2. 2Department of Cell and Developmental Biology, University College London, London, UK


Introduction The preferential vulnerability of striatal medium spiny neurons is a pathological hallmark in Huntington’s Disease (HD). Striatal neurons have been proposed to differ from other less vulnerable neuronal populations, namely in their proteostasis of mutant huntingtin (mHtt) and in mitochondrial function. However, it remains unclear whether and how these differences interact to condition neuronal survival.

Aims Assess how mHtt proteostasis and mitochondrial function change over time in striatal vs. cortical neurons, and whether they correlate with vulnerability.

Methods Longitudinal survival analysis in neuronal HD models expressing mHtt was performed using fluorescence microscopy. NAD(P)H levels were measured using fluorescence lifetime imaging and oxygen consumption was measured using cell respirometry.

Results In striatal and cortical neurons, mHtt inclusion body (IB) formation correlated with higher survival and lower risk of mitochondrial membrane potential (MMP) loss. Striatal neurons displayed higher risks of death and of MMP loss, despite having lower levels of mHtt than their cortical counterparts, which correlated with a lower risk of IB formation. The mHtt concentration threshold for IB formation was similar in striatal and cortical neurons. Striatal neurons presented lower levels of NAD(P)H and reduced maximal respiration capacity.

Conclusion The higher vulnerability of striatal neurons in HD may be attributed to a decreased ability to cope with a soluble and toxic form of mHtt due to a combination of lower risk of IB formation and lower energetic resources.

Acknowledgements Fundação para a Ciência e a Tecnologia P2020-PTDC/NEU-NMC/0412/2014, POCI-01-0145-FEDER- 016577, 3599-PPCDT; SFRH/BD/108733/2015; UID/QUI/50006/2013

  • huntingtin
  • proteostasis
  • mitochondria

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.