The Postsynaptic Scaffolding Protein SAPAP3 Shapes Mitochondrial Activity: The Case of Huntington's Disease

Authors

• Patrícia Coelho, University of Coimbra
• Ildete Luísa Ferreira, University of Coimbra
• Ana Sofia Lourenço, Biocant—Biotechnology Innovation Center, Cantanhede, Portugal
• Daniela Marinho, University of Coimbra
• Sandra Isabel Anjo, University of Coimbra
• Zongwei Fang, University of Coimbra
• Lígia Fão, University of Coimbra
• Sandra I. Mota, University of Coimbra
• Philippe J. Mas, European Molecular Biology Laboratory
• Mário Carvalho, University of Copenhagen
• Rui Jorge Nobre, University of Coimbra
• Carina Henriques, University of Coimbra
• Joana Fraga, Universidade do Porto
• Dongqing Wang, Massachusetts Institute of Technology
• Sandra Macedo Ribeiro, Universidade do Porto
• Luís Pereira de Almeida, University of Coimbra
• Patrícia Monteiro, University of Minho
• Isaura Simões, Old Dominion UniversityFollow
• Darren J. Hart, Université Grenoble Alpes
• Bruno Manadas, University of Coimbra
• João Peça, University of Coimbra
• Pedro Castanheira, Biocant—Biotechnology Innovation Center, Cantanhede, Portugal
• A. Cristina Rego, University of Coimbra

Document Type

Article

Publication Date

2026

DOI

10.1038/s41419-026-09156-4

Publication Title

Cell Death & Disease

Volume

Advance online publication

Pages

56 pp.

Abstract

Postsynaptic scaffolding protein SAP90/PSD95-associated protein 3 (SAPAP3) modulates cortico-striatal signalling and regulates the maintenance of synaptic structure. Notably, SAPAP3 defects have been reported in several human psychiatric disorders that share pathophysiological features with Huntington’s disease (HD), a neurodegenerative disorder characterized by the expression of mutant huntingtin (mHTT) and marked dysfunction of cortico-striatal synapses and mitochondria. However, the role of SAPAP3 in mitochondrial function and HD pathophysiology remains unexplored. SAPAP3 was extracted from striatal synaptoneurosomes and analyzed by SWATH-MS proteomics to identify potential interactors, revealing SAPAP3 association with several mitochondrial proteins, particularly Mic60. These data were further complemented with proximity ligation assay (PLA) and immunoprecipitation experiments, supporting a direct or indirect interaction between SAPAP3 and Mic60. SAPAP3 knockout (SAPAP3-KO) mouse striatum exhibited reduced Mic60 protein levels, decreased mitochondrial respiratory chain activity and Ca²⁺ uptake, as well as increased mitochondrial roundness and circularity, accompanied by decreased perimeter and area, consistent with mitochondrial fragmentation. Analysis of SAPAP3 protein levels in postmortem caudate tissue from HD patients, striatal tissue and isolated mitochondria from YAC128 mice, as well as mitochondria in primary striatal YAC128 neurons and STHdh Q111 cells, showed consistently reduced SAPAP3 levels. HD cells and WT cells subjected to SAPAP3 silencing showed alterations in mitochondrial morphology, movement and function. In contrast, HD striatal cells transfected with ovSAPAP3 constructs to restore SAPAP3 levels showed a rescue of mitochondrial morphology, motility, function and Ca2+ handling, together with decreased levels of reactive oxygen species (ROS). These findings uncover a novel role for postsynaptic scaffolding protein SAPAP3 in preserving mitochondrial health, particularly mitochondrial dynamics and function, under neuropathological conditions characterized by mitochondrial abnormalities such as HD.

Rights

© 2026 The Authors.

This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original authors and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Data Availability

Article states: "All data generated and analysed in this study are included in this published article and supplementary information file. Mass spectrometry proteomics data were deposited at the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD023969. All remaining data can be made available upon reasonable request."

Original Publication Citation

Coelho, P., Ferreira, I. L., Lourenço, A. S., Marinho, D., Anjo, S. I., Fang, Z., Fão, L., Mota, S. I., Mas, P. J., Carvalho, M., Nobre, R. J., Henriques, C., Fraga, J., Wang, D., Ribeiro, S. M., Pereira de Almeida, L., Monteiro, P., Simões, I., Hart, D. J.,…Rego, A. C. (2026). The postsynaptic scaffolding protein SAPAP3 shapes mitochondrial activity: The case of Huntington’s disease. Cell Death & Disease. Advance online publication. https://doi.org/10.1038/s41419-026-09156-4

Repository Citation

Coelho, Patrícia; Ferreira, Ildete Luísa; Lourenço, Ana Sofia; Marinho, Daniela; Anjo, Sandra Isabel; Fang, Zongwei; Fão, Lígia; Mota, Sandra I.; Mas, Philippe J.; Carvalho, Mário; Nobre, Rui Jorge; Henriques, Carina; Fraga, Joana; Wang, Dongqing; Ribeiro, Sandra Macedo; Almeida, Luís Pereira de; Monteiro, Patrícia; Simões, Isaura; Hart, Darren J.; Manadas, Bruno; Peça, João; Castanheira, Pedro; and Rego, A. Cristina, "The Postsynaptic Scaffolding Protein SAPAP3 Shapes Mitochondrial Activity: The Case of Huntington's Disease" (2026). Biological Sciences Faculty Publications. 708.
https://digitalcommons.odu.edu/biology_fac_pubs/708

ORCID

0000-0002-9331-6340 (Simões)