NeuronalSNCAtranscription during Lewy body formation

ABSTRACT Background 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. Methods SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in 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). Results SNCA transcripts in neurons with punctate α-syn immunoreactivity were preserved both in the substantia nigra and amygdala but were reduced in neurons with compact α-syn inclusions. Only single SNCA transcripts were detected in astrocytes with or without 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. Conclusions The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies provides 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 support a therapeutic strategy incorporating a finely tuned dual approach targeting the elimination of misfolded α-syn along with the reduction of the SNCA transcription to avoid feeding of pathological α-syn seeding.