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

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.

Kon T ，Forrest SL ，Lee S ，Li J ，Chasiotis H ，Nassir N ，Uddin MJ ，Lang AE ，Kovacs GG ... -  《-》

Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models.

Mavroeidi P ，Arvanitaki F ，Vetsi M ，Becker S ，Vlachakis D ，Jensen PH ，Stefanis L ，Xilouri M ... -  《-》

Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models.

Mavroeidi P ，Arvanitaki F ，Karakitsou AK ，Vetsi M ，Kloukina I ，Zweckstetter M ，Giller K ，Becker S ，Sorrentino ZA ，Giasson BI ，Jensen PH ，Stefanis L ，Xilouri M ... -  《-》

Relocation of p25α/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy.

Ota K ，Obayashi M ，Ozaki K ，Ichinose S ，Kakita A ，Tada M ，Takahashi H ，Ando N ，Eishi Y ，Mizusawa H ，Ishikawa K ... -  《Acta Neuropathologica Communications》

Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy?

De Nuccio F ，Kashyrina M ，Serinelli F ，Laferrière F ，Lofrumento DD ，De Giorgi F ，Ichas F ... -  《Biomolecules》