The postsynaptic scaffolding protein SAPAP3 shapes mitochondrial activity: the case of Huntington’s disease
16 affiliations
- 1CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- 2III-UC—Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
- 3Biocant—Biotechnology Innovation Center, Cantanhede, Portugal
- 4FMUC—Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- 5EMBL—European Molecular Biology Laboratory, Grenoble, France
- 6ISBG—Integrated Structural Biology Grenoble, CNRS, CEA, Université Grenoble Alpes, EMBL, Grenoble, France
- 7Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
- 8ViraVector—Viral Vectors for Gene Transfer Core Facility, University of Coimbra, Coimbra, Portugal
- 9i3S—Instituto de Investigação e Inovação em Saúde Portugal, Universidade do Porto, Porto, Portugal
- 10McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA USA
- 11Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
- 12Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- 13Department of Biological Sciences, Old Dominion University, Norfolk, VA USA
- 14Institut de Biologie Structurale, CEA, CNRS, Université Grenoble Alpes, Grenoble, France
- 15Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal
- 16Present Address: Immunethep SA, Biocant Park, Nucleo 4, Cantanhede, Portugal
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.
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BibTeX
@article{coelho2026postsynaptic,
title = {{The postsynaptic scaffolding protein SAPAP3 shapes mitochondrial activity: the case of Huntington’s disease}},
author = {Patrícia Coelho and Ildete Luísa Ferreira and Ana Sofia Lourenço and Daniela Marinho and Sandra Isabel Anjo and Zongwei Fang and Lígia Fão and Sandra I. Mota and Philippe J. Mas and Mário Carvalho and Rui Jorge Nobre and Carina Henriques and Joana Fraga and Dongqing Wang and Sandra Macedo Ribeiro and Luís Pereira de Almeida and Patrícia Monteiro and Isaura Simões and Darren J. Hart and Bruno Manadas and João Peça and Pedro Castanheira and A. Cristina Rego},
journal = {Cell Death \& Disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09156-4},
url = {https://doi.org/10.1038/s41419-026-09156-4},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The postsynaptic scaffolding protein SAPAP3 shapes mitochondrial activity: the case of Huntington’s disease
AU - Patrícia Coelho
AU - Ildete Luísa Ferreira
AU - Ana Sofia Lourenço
AU - Daniela Marinho
AU - Sandra Isabel Anjo
AU - Zongwei Fang
AU - Lígia Fão
AU - Sandra I. Mota
AU - Philippe J. Mas
AU - Mário Carvalho
AU - Rui Jorge Nobre
AU - Carina Henriques
AU - Joana Fraga
AU - Dongqing Wang
AU - Sandra Macedo Ribeiro
AU - Luís Pereira de Almeida
AU - Patrícia Monteiro
AU - Isaura Simões
AU - Darren J. Hart
AU - Bruno Manadas
AU - João Peça
AU - Pedro Castanheira
AU - A. Cristina Rego
PY - 2026
DA - 2026/08/07
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09156-4
UR - https://doi.org/10.1038/s41419-026-09156-4
AB - 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.
SN - 2041-4889
ER -