Nuclear aggregates of NONO/SFPQ and A-to-I-edited RNA in Parkinson's disease and dementia with Lewy bodies

• Published in: Neuron (Cambridge, Mass.) Vol. 112; no. 15; p. 2558
• Main Authors: Belur, Nandkishore R, Bustos, Bernabe I, Lubbe, Steven J, Mazzulli, Joseph R
• Format: Journal Article
• Language: English
• Published: United States 07-08-2024
• Subjects: Adenosine - metabolism; Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Aged; Aged, 80 and over; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Cell Nucleus - metabolism; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Female; Humans; Inosine - metabolism; Lewy Body Disease - genetics; Lewy Body Disease - metabolism; Lewy Body Disease - pathology; Male; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; PTB-Associated Splicing Factor - genetics; PTB-Associated Splicing Factor - metabolism; RNA Editing; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; iPSC models; RNA editing; inverted Alu repeats; protein aggregation; neurodegeneration; synucleinopathies; nuclear retention; Lewy bodies; RNA binding proteins
• ISSN: 1097-4199
• DOI: 10.1016/j.neuron.2024.05.003

Neurodegenerative diseases are commonly classified as proteinopathies that are defined by the aggregation of a specific protein. Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are classified as synucleinopathies since α-synuclein (α-syn)-containing inclusions histopathologically define these diseases. Unbiased biochemical analysis of PD and DLB patient material unexpectedly revealed novel pathological inclusions in the nucleus comprising adenosine-to-inosine (A-to-I)-edited mRNAs and NONO and SFPQ proteins. These inclusions showed no colocalization with Lewy bodies and accumulated at levels comparable to α-syn. NONO and SFPQ aggregates reduced the expression of the editing inhibitor ADAR3, increasing A-to-I editing mainly within human-specific, Alu-repeat regions of axon, synaptic, and mitochondrial transcripts. Inosine-containing transcripts aberrantly accumulated in the nucleus, bound tighter to recombinant purified SFPQ in vitro, and potentiated SFPQ aggregation in human dopamine neurons, resulting in a self-propagating pathological state. Our data offer new insight into the inclusion composition and pathophysiology of PD and DLB.