NeuronalSNCAtranscription during Lewy body formation

Abstract

ABSTRACTBackgroundMisfolded 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 ofSNCAin 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 onSNCAtranscripts in various α-syn immunoreactive cytopathologies.MethodsSNCAtranscripts 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 specificSNCAexpression in non-diseased frontal cortex (n = 3).ResultsSNCAtranscripts 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 singleSNCAtranscripts 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 expressedSNCAtranscripts, while expression was largely absent in astrocytes and microglia.ConclusionsThe preserved cellularSNCAexpression 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 ofSNCAproduction 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 theSNCAtranscription to avoid feeding of pathological α-syn seeding.