The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration
8 affiliations
- 1Teitur Trophics ApS, 8200 Aarhus N, Denmark
- 2Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark
- 3Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
- 4Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
- 5Quantlmed Ltd, Canterbury, Kent UK
- 6Fosgerau Consult ApS, 2720 Vanløse, Denmark
- 7School of Medicine and Population Health, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
- 8Naason Science Inc, 123 Saengmyung-ro, Cheongju-si, South Korea
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40478-026-02403-x.
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BibTeX
@article{dalby2026sorcs2derived,
title = {{The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration}},
author = {Anders Dalby and Mathias Kaas and Johan Palmfeldt and Mads Graversgaard and Sanne Nordestgaard and Christian R. O. Bartling and Kasper Budolph and Neil Benson and Emily Roashan and Søren L. Pedersen and Heather Mortiboys and Larry C. Park and Simon Glerup and Kristian Strømgaard and Keld Fosgerau and Simon Mølgaard},
journal = {Acta Neuropathologica Communications},
year = {2026},
month = aug,
doi = {10.1186/s40478-026-02403-x},
url = {https://doi.org/10.1186/s40478-026-02403-x},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration
AU - Anders Dalby
AU - Mathias Kaas
AU - Johan Palmfeldt
AU - Mads Graversgaard
AU - Sanne Nordestgaard
AU - Christian R. O. Bartling
AU - Kasper Budolph
AU - Neil Benson
AU - Emily Roashan
AU - Søren L. Pedersen
AU - Heather Mortiboys
AU - Larry C. Park
AU - Simon Glerup
AU - Kristian Strømgaard
AU - Keld Fosgerau
AU - Simon Mølgaard
PY - 2026
DA - 2026/08/10
JO - Acta Neuropathologica Communications
DO - 10.1186/s40478-026-02403-x
UR - https://doi.org/10.1186/s40478-026-02403-x
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40478-026-02403-x.
SN - 2051-5960
ER -