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Huntingtin and its allies at the cortico-striatal synapse
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  • Review Article
  • Open access
  • Published: 27 March 2026

Huntingtin and its allies at the cortico-striatal synapse

  • Chiara Zuccato  ORCID: orcid.org/0000-0003-1771-33921,2,
  • Andrea Scolz1,2 &
  • Raffaele Iennaco1,2 

Cell Death & Disease , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Huntington's disease
  • Mechanisms of disease
  • Protein–protein interaction networks
  • Synaptic plasticity
  • Synaptic transmission

Abstract

Huntington’s Disease (HD) is characterized by progressive motor and cognitive decline, largely driven by cortico-striatal synaptic dysfunction. Central to these processes is huntingtin (HTT) protein, which is abundantly present at the synapse. HTT regulates the synaptic vesicle cycle at presynaptic terminals and serves as a scaffold at the postsynaptic density where it modulates receptor dynamics. An expanding network of HTT-interacting proteins (HIPs), crucial for maintaining synaptic structure and function, underscores the role of HTT as a core component of synaptic integrity. This review examines the 30-year research journey that has unveiled HTT pre- and postsynaptic partners, with focus on experimentally validated interactors and their involvement in HD cortico-striatal synaptic dysfunction.

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Acknowledgements

We are deeply grateful to the families living with Huntington’s disease, whose strength and resilience continue to inspire our research. We thank Elena Cattaneo for suggestions.

Funding

This work was supported by grants from the Telethon Foundation (GGP13053 and GGP20067 to CZ) and the Italian Ministry of Education, University and Research (PRIN 20128XWKTX and PRIN 2022 PNRR P2022J2BWE_003 to CZ).

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Authors and Affiliations

  1. Department of Biosciences, University of Milan, Milan, Italy

    Chiara Zuccato, Andrea Scolz & Raffaele Iennaco

  2. Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milan, Italy

    Chiara Zuccato, Andrea Scolz & Raffaele Iennaco

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  1. Chiara Zuccato
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  2. Andrea Scolz
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  3. Raffaele Iennaco
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CZ wrote the article with contribution from AS and RI. CZ, RI and AS designed the figures.

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Correspondence to Chiara Zuccato.

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Zuccato, C., Scolz, A. & Iennaco, R. Huntingtin and its allies at the cortico-striatal synapse. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08584-6

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  • Received: 31 July 2025

  • Revised: 30 January 2026

  • Accepted: 06 March 2026

  • Published: 27 March 2026

  • DOI: https://doi.org/10.1038/s41419-026-08584-6

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