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

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Multiple System Atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated alpha-synuclein (α-syn) in oligodendrocytes.
• The precise origin of α-syn accumulation in GCIs, whether from endogenous overexpression or neuronal sources, remains unclear.
• Tubulin polymerization promoting protein (TPPP) is implicated in GCI pathology.

Purpose of the Study:

• To investigate the origin of α-syn accumulation in GCIs in MSA.
• To evaluate the expression patterns of SNCA and TPPP transcripts in neurons and oligodendrocytes in MSA and control cases.
• To explore the potential synergistic role of SNCA and TPPP in GCI formation.

Main Methods:

• RNAscope with immunofluorescence was used to quantify SNCA and TPPP transcript densities in autopsy brain tissues from MSA and control cases.
• Single-nucleus RNA-sequencing data was analyzed for TPPP expression in control frontal cortex.
• Transcript localization and density were assessed in neuronal and oligodendrocyte cell bodies, nuclei, and cytoplasm.

Main Results:

• SNCA and TPPP transcripts were detected in both neurons and oligodendrocytes, with higher densities in GCIs and glial nuclear inclusions in MSA.
• TPPP transcripts were unexpectedly found in neurons, despite a lack of detectable TPPP protein.
• Single-nucleus RNA-sequencing confirmed TPPP expression in oligodendrocytes and also in excitatory and inhibitory neurons.

Conclusions:

• Elevated SNCA transcript levels may provide templates for misfolded α-syn in MSA pathogenesis.
• The parallel expression patterns of SNCA and TPPP transcripts suggest a synergistic role in GCI formation.
• Targeting SNCA and TPPP transcripts presents a potential avenue for future molecular therapies for MSA.