{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal",
    "III-UC—Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal",
    "Biocant—Biotechnology Innovation Center, Cantanhede, Portugal",
    "FMUC—Faculty of Medicine, University of Coimbra, Coimbra, Portugal",
    "EMBL—European Molecular Biology Laboratory, Grenoble, France",
    "ISBG—Integrated Structural Biology Grenoble, CNRS, CEA, Université Grenoble Alpes, EMBL, Grenoble, France",
    "Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark",
    "ViraVector—Viral Vectors for Gene Transfer Core Facility, University of Coimbra, Coimbra, Portugal",
    "i3S—Instituto de Investigação e Inovação em Saúde Portugal, Universidade do Porto, Porto, Portugal",
    "McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA USA",
    "Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal",
    "Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal",
    "Department of Biological Sciences, Old Dominion University, Norfolk, VA USA",
    "Institut de Biologie Structurale, CEA, CNRS, Université Grenoble Alpes, Grenoble, France",
    "Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal",
    "Present Address: Immunethep SA, Biocant Park, Nucleo 4, Cantanhede, Portugal"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 23,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Patrícia Coelho",
      "orcid": "0000-0002-8647-4658"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ildete Luísa Ferreira"
    },
    {
      "affs": [
        2
      ],
      "name": "Ana Sofia Lourenço",
      "orcid": "0000-0001-9459-3561"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Daniela Marinho",
      "orcid": "0000-0002-4124-6483"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sandra Isabel Anjo",
      "orcid": "0000-0003-2180-3518"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zongwei Fang"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Lígia Fão"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sandra I. Mota"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Philippe J. Mas"
    },
    {
      "affs": [
        6
      ],
      "name": "Mário Carvalho"
    },
    {
      "affs": [
        0,
        1,
        7
      ],
      "name": "Rui Jorge Nobre"
    },
    {
      "affs": [
        0,
        7
      ],
      "name": "Carina Henriques"
    },
    {
      "affs": [
        8
      ],
      "name": "Joana Fraga"
    },
    {
      "affs": [
        9
      ],
      "name": "Dongqing Wang"
    },
    {
      "affs": [
        8
      ],
      "name": "Sandra Macedo Ribeiro"
    },
    {
      "affs": [
        0,
        7,
        10
      ],
      "name": "Luís Pereira de Almeida",
      "orcid": "0000-0001-5831-3307"
    },
    {
      "affs": [
        11
      ],
      "name": "Patrícia Monteiro"
    },
    {
      "affs": [
        0,
        12
      ],
      "name": "Isaura Simões",
      "orcid": "0000-0002-9331-6340"
    },
    {
      "affs": [
        4,
        13
      ],
      "name": "Darren J. Hart",
      "orcid": "0000-0002-3502-2002"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Bruno Manadas",
      "orcid": "0000-0002-2087-4042"
    },
    {
      "affs": [
        0,
        14
      ],
      "name": "João Peça"
    },
    {
      "affs": [
        2,
        15
      ],
      "name": "Pedro Castanheira"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "A. Cristina Rego",
      "orcid": "0000-0003-0700-3776"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9jw39xvfkv7qz.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09156-4",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13731651/",
  "id": "9jw39xvfkv7qz",
  "issns": [
    "2041-4889"
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  "landing_url": "https://doi.org/10.1038/s41419-026-09156-4",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
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      "openalex",
      "2804|Genetic Neurodegenerative Diseases"
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  "openalex": "W7197015122",
  "pdf_url": "https://www.nature.com/articles/s41419-026-09156-4_reference.pdf",
  "pmcid": "PMC13731651",
  "pmid": "42977731",
  "published": "2026-08-07",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/9jw39xvfkv7qz.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:21:48Z",
      "native_id": "PMC13731651",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41419-026-09156-4"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Genetic Neurodegenerative Diseases",
      "subfield": "neuroscience"
    }
  ],
  "title": "The postsynaptic scaffolding protein SAPAP3 shapes mitochondrial activity: the case of Huntington’s disease",
  "title_text": "The postsynaptic scaffolding protein SAPAP3 shapes mitochondrial activity: the case of Huntington’s disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:21:48Z",
  "url": "https://research.draconitic.com/paper/9jw39xvfkv7qz",
  "venue": "Cell Death & Disease",
  "versions": []
}