Cell-specific mitochondrial response in progressive supranuclear palsy

Affiliations

¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
² Centre for Applied and Translational Genomics (CATG), Mohammed Bin Rashid University of Medicine and Health Sciences, United Arab Emirates.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada.
⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada; Rossy Centre for PSP, Toronto Western Hospital, Toronto M5T 2S8 Ontario, Canada; Department of Neurology, University of Toronto, Toronto M5T 1A8 Ontario, Canada.
⁶ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Rossy Centre for PSP, Toronto Western Hospital, Toronto M5T 2S8 Ontario, Canada; Department of Neurology, University of Toronto, Toronto M5T 1A8 Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, M5T 2S8 Toronto, Ontario, Canada.
⁷ Centre for Applied and Translational Genomics (CATG), Mohammed Bin Rashid University of Medicine and Health Sciences, United Arab Emirates; GenomeArc Inc., Mississauga, ON, Canada.
⁸ The University of Manchester, Manchester, UK.
⁹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Rossy Centre for PSP, Toronto Western Hospital, Toronto M5T 2S8 Ontario, Canada; Department of Neurology, University of Toronto, Toronto M5T 1A8 Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, M5T 2S8 Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Laboratory Medicine Program, University Health Network, Toronto, Canada. Electronic address: gabor.kovacs@uhn.ca.

PMID: 40254117
DOI: 10.1016/j.mito.2025.102043

Free article

Cell-specific mitochondrial response in progressive supranuclear palsy

Valerie Sackmann et al. Mitochondrion. 2025 Sep.

Free article

. 2025 Sep:84:102043.

doi: 10.1016/j.mito.2025.102043. Epub 2025 Apr 18.

Affiliations

¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
² Centre for Applied and Translational Genomics (CATG), Mohammed Bin Rashid University of Medicine and Health Sciences, United Arab Emirates.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada.
⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada; Rossy Centre for PSP, Toronto Western Hospital, Toronto M5T 2S8 Ontario, Canada; Department of Neurology, University of Toronto, Toronto M5T 1A8 Ontario, Canada.
⁶ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Rossy Centre for PSP, Toronto Western Hospital, Toronto M5T 2S8 Ontario, Canada; Department of Neurology, University of Toronto, Toronto M5T 1A8 Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, M5T 2S8 Toronto, Ontario, Canada.
⁷ Centre for Applied and Translational Genomics (CATG), Mohammed Bin Rashid University of Medicine and Health Sciences, United Arab Emirates; GenomeArc Inc., Mississauga, ON, Canada.
⁸ The University of Manchester, Manchester, UK.
⁹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Krembil Brain Institute, University Health Network, Toronto M5T 0S8 Ontario, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Rossy Centre for PSP, Toronto Western Hospital, Toronto M5T 2S8 Ontario, Canada; Department of Neurology, University of Toronto, Toronto M5T 1A8 Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, M5T 2S8 Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Laboratory Medicine Program, University Health Network, Toronto, Canada. Electronic address: gabor.kovacs@uhn.ca.

PMID: 40254117
DOI: 10.1016/j.mito.2025.102043

Abstract

Progressive supranuclear palsy (PSP) is a main form of idiopathic tauopathy characterized neuropathologically by subcortical neurofibrillary tangles in neurons, oligodendroglial coiled bodies, and tufted astrocytes, which follow sequential distribution in the human brain. Mitochondrial dysfunction is thought to be a contributor to many neurodegenerative diseases, but its role in PSP at the cellular level remains incompletely understood. To address this, we performed cell-specific morphometric analysis of mitochondrial markers in post-mortem tissues from motor cortex of PSP patients and non-diseased controls (n = 5 each) followed by single-nuclear transcriptomics (n = 3 each) to identify changes in genes that regulate mitochondrial function. We treated iCell astrocytes with PSP brain homogenates and isolated viable astrocytes from multiple regions of PSP-affected brains. We found that PSP is characterized by significant mitochondrial changes in neurons and astrocytes at the immunohistochemical level, particularly in complex I, with distinct transcriptomic responses across cell types. Glial cells exhibited upregulation of pathways associated with mitochondrial function. In contrast, excitatory and inhibitory neurons showed downregulation in these pathways, indicating impaired mitochondrial function. Astrocytes derived from different human brain regions express varied levels of GFAP and EAAT1 immunoreactivity. Astrocytic tau pathology in cell culture derived from postmortem PSP brains mirrors that seen in corresponding brain tissue histology. Tau pathology in human astrocyte cell culture is associated with clumps of mitochondria potentially associated with impairment in their neuron supportive function. Our results underscore selective complex I damage and cell-type specific patterns that differentiate PSP from other neurodegenerative diseases.

Keywords: Astroglia; Cell culture; Mitochondria; Progressive supranuclear palsy; Single-nuclei RNA sequencing; Tau.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [VS is/was an employee of Rewind Therapeutics NV. SLF receives funding from the National Health and Medical Research Council, Australia outside the submitted work. IMV has a pending patent for Diagnostic assays for movement disorders (18/537,455) and receives funding from the Michael J. Fox Foundation. MCT receives funding from NIH, Weston Brain Foundation, Tanenbaum Institute for Research in Science of Sport, Canadian Institutes of Health Research, and in-kind funding from Roche; she has served as an advisor to Eisai, Lilly and Novo Nordisk; she conducts clinical trials for Biogen, Anavex, Janssen, Novo Nordisk, Merck, Green Valley, UCB. AEL has served as an advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, BMS, Denali, Janssen, Lilly, Pharma 2B, Sun Pharma, and UCB; received honoraria from Sun Pharma, and AbbVie; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, Parkinson Foundation, and Parkinson Canada; received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. GGK reports personal fees from Parexel and Mitsubishi-Tanabe, other funding from Rossy Family Foundation, from Edmond Safra Foundation, grants from Krembil Foundation, MSA Coalition, MJ Fox Foundation, Parkinson Canada, NIH, Canada Foundation for Innovation, and Ontario Research Fund outside the submitted work; in addition, GGK has a shared patent for 5G4 Synuclein antibody and a pending patent for Diagnostic assays for movement disorders (18/537,455), and received royalties from Wiley, Cambridge, and Elsevier publishers].

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Cell-specific mitochondrial response in progressive supranuclear palsy

Affiliations

Cell-specific mitochondrial response in progressive supranuclear palsy

Authors

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Abstract

Conflict of interest statement

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Medical

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