SNCA and TPPP transcripts increase in oligodendroglial cytoplasmic inclusions in multiple system atrophy

Tomoya Kon; Shelley L. Forrest; Seojin Lee; Jun Li; Helen Chasiotis; Nasna Nassir; Mohammed J. Uddin; Anthony E. Lang; Gabor G. Kovacs

Neurobiology of Disease (Aug 2024)

SNCA and TPPP transcripts increase in oligodendroglial cytoplasmic inclusions in multiple system atrophy

Tomoya Kon,
Shelley L. Forrest,
Seojin Lee,
Jun Li,
Helen Chasiotis,
Nasna Nassir,
Mohammed J. Uddin,
Anthony E. Lang,
Gabor G. Kovacs

Affiliations

Tomoya Kon: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
Shelley L. Forrest: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada
Seojin Lee: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Jun Li: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
Helen Chasiotis: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
Nasna Nassir: Centre for Applied and Translational Genomics, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
Mohammed J. Uddin: Centre for Applied and Translational Genomics, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates; GenomeArc Inc, Toronto, ON, Canada
Anthony E. Lang: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Edmund J Safra Program in Parkinson's Disease and Rossy Progressive Supranuclear Palsy Centre, Toronto Western Hospital, Toronto, ON, Canada; Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada
Gabor G. Kovacs: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Edmund J Safra Program in Parkinson's Disease and Rossy Progressive Supranuclear Palsy Centre, Toronto Western Hospital, Toronto, ON, Canada; Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada; Corresponding author at: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Journal volume & issue: Vol. 198
p. 106551

Abstract

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Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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