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

Nandkishore R Belur; Bernabe I Bustos; Steven J Lubbe; Joseph R Mazzulli

doi:10.1016/j.neuron.2024.05.003

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

Neuron. 2024 May 16:S0896-6273(24)00328-3. doi: 10.1016/j.neuron.2024.05.003. Online ahead of print.

Authors

Nandkishore R Belur¹, Bernabe I Bustos¹, Steven J Lubbe², Joseph R Mazzulli³

Affiliations

¹ The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
² The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
³ The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: jmazzulli@northwestern.edu.

PMID: 38761794
DOI: 10.1016/j.neuron.2024.05.003

Abstract

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.

Keywords: Lewy bodies; RNA binding proteins; RNA editing; iPSC models; inverted Alu repeats; neurodegeneration; nuclear retention; protein aggregation; synucleinopathies.