{
  "abstract": "Mitochondria are critical for sustaining the high energy demands of neuronal activity and their dysregulation is a hallmark of neurodegeneration. Targeting pathways of neurotrophic signaling is a well-established therapeutic strategy to enhance mitochondrial function and mitigate neurodegeneration. The VPS10p domain receptor, SorCS2, has recently emerged as a receptor with neurotrophic signaling capabilities. Here, we design and develop novel SorCS2-derived macrocyclic peptides mimicking receptor activation in vivo. We show that SorCS2-peptides enhance both neurotrophic support and boost metabolism by activating both CREB and AMPK potentially via a CAMKK2-dependent mechanism. This leads to upregulation of the mitochondrial and lysosomal master regulators, PGC1α and TFEB. Treating the zQ175 mouse model of Huntington’s Disease with a lipidated SorCS2 macrocycle, TT-P34, rescues motor and behavioral deficits and preserves synaptic and mitochondrial signatures in the striatum. In addition, treatment of the mitochondria-deficient MPTP-induced mouse model of Parkinson’s Disease leads to amelioration of motor deficits and preserves dopaminergic neurons. Finally, we demonstrate that TT-P34 crosses the blood-brain barrier in non-human primates and estimate a human therapeutic dosing regimen by pharmacodynamic modelling. Together, our findings support the use of TT-P34 as a novel disease-modifying therapy targeting SorCS2-receptor pathway to prevent neurodegeneration.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40478-026-02403-x.",
  "abstract_shown": true,
  "affiliations": [
    "Teitur Trophics ApS, 8200 Aarhus N, Denmark",
    "Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark",
    "Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark",
    "Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark",
    "Quantlmed Ltd, Canterbury, Kent UK",
    "Fosgerau Consult ApS, 2720 Vanløse, Denmark",
    "School of Medicine and Population Health, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK",
    "Naason Science Inc, 123 Saengmyung-ro, Cheongju-si, South Korea"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Anders Dalby",
      "orcid": "0000-0002-2255-1335"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Mathias Kaas"
    },
    {
      "affs": [
        2
      ],
      "name": "Johan Palmfeldt"
    },
    {
      "affs": [
        1
      ],
      "name": "Mads Graversgaard"
    },
    {
      "affs": [
        0
      ],
      "name": "Sanne Nordestgaard"
    },
    {
      "affs": [
        3
      ],
      "name": "Christian R. O. Bartling"
    },
    {
      "affs": [
        0
      ],
      "name": "Kasper Budolph"
    },
    {
      "affs": [
        4
      ],
      "name": "Neil Benson"
    },
    {
      "affs": [
        4
      ],
      "name": "Emily Roashan"
    },
    {
      "affs": [
        5
      ],
      "name": "Søren L. Pedersen"
    },
    {
      "affs": [
        6
      ],
      "name": "Heather Mortiboys"
    },
    {
      "affs": [
        7
      ],
      "name": "Larry C. Park"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Simon Glerup"
    },
    {
      "affs": [
        3
      ],
      "name": "Kristian Strømgaard"
    },
    {
      "affs": [
        5
      ],
      "name": "Keld Fosgerau"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Simon Mølgaard"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5w18cfyhc5by5.bib",
  "cited_by": 0,
  "doi": "10.1186/s40478-026-02403-x",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13746749/",
  "id": "5w18cfyhc5by5",
  "issns": [
    "2051-5960"
  ],
  "landing_url": "https://doi.org/10.1186/s40478-026-02403-x",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2804|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W4414272929",
  "pdf_url": null,
  "pmcid": "PMC13746749",
  "pmid": "43000407",
  "published": "2026-08-10",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/5w18cfyhc5by5.ris",
  "sources": [
    {
      "first_seen": "2026-11-11T12:24:04Z",
      "native_id": "PMC13746749",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s40478-026-02403-x"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    }
  ],
  "title": "The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration",
  "title_text": "The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration",
  "type": "peer-reviewed",
  "updated_at": "2026-11-13T12:23:24Z",
  "url": "https://research.draconitic.com/paper/5w18cfyhc5by5",
  "venue": "Acta Neuropathologica Communications",
  "versions": []
}