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Open Access 01-12-2023 | Parkinson's Disease | Research

Neuronal SNCA transcription during Lewy body formation

Authors: Tomoya Kon, Shelley L. Forrest, Seojin Lee, Ivan Martinez‑Valbuena, Jun Li, Nasna Nassir, Mohammed J. Uddin, Anthony E. Lang, Gabor G. Kovacs

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Misfolded α-synuclein (α-syn) is believed to contribute to neurodegeneration in Lewy body disease (LBD) based on considerable evidence including a gene-dosage effect observed in relation to point mutations and multiplication of SNCA in familial Parkinson’s disease. A contradictory concept proposes early loss of the physiological α-syn as the major driver of neurodegeneration. There is a paucity of data on SNCA transcripts in various α-syn immunoreactive cytopathologies. Here, the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD (n = 5) were evaluated using RNAscope combined with immunofluorescence for disease-associated α-syn. Single-nucleus RNA sequencing was performed to elucidate cell-type specific SNCA expression in non-diseased frontal cortex (n = 3). SNCA transcripts were observed in the neuronal nucleus and cytoplasm in neurons without α-syn, those containing punctate α-syn immunoreactivity, irregular-shaped compact inclusion, and brainstem-type and cortical-type LBs. However, SNCA transcripts were only rarely found in the α-syn immunoreactive LB areas. The total cell body SNCA transcript area densities in neurons with punctate α-syn immunoreactivity were preserved but were significantly reduced in neurons with compact α-syn inclusions both in the substantia nigra and amygdala. This reduction was also observed in the cytoplasm but not in the nucleus. Only single SNCA transcripts were detected in astrocytes with or without disease-associated α-syn immunoreactivity in the amygdala. Single-nucleus RNA sequencing revealed that excitatory and inhibitory neurons, oligodendrocyte progenitor cells, oligodendrocytes, and homeostatic microglia expressed SNCA transcripts, while expression was largely absent in astrocytes and microglia. The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies might provide a pool for local protein production that can aggregate and serve as a seed for misfolded α-syn. Successful segregation of disease-associated α-syn is associated with the exhaustion of SNCA production in the terminal cytopathology, the Lewy body. Our observations inform therapy development focusing on targeting SNCA transcription in LBD.

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Title: Neuronal SNCA transcription during Lewy body formation
Authors: Tomoya Kon
Shelley L. Forrest
Seojin Lee
Ivan Martinez‑Valbuena
Jun Li
Nasna Nassir
Mohammed J. Uddin
Anthony E. Lang
Gabor G. Kovacs
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Parkinson's Disease
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01687-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neuronal SNCA transcription during Lewy body formation

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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