Nuclear aggregates of NONO/SFPQ and A-to-I-edited RNA in Parkinson's disease and dementia with Lewy bodies.
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 ?-synuclein (?-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 ?-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.
Mesh Terms:
Adenosine, Adenosine Deaminase, Aged, Aged, 80 and over, Cell Nucleus, Dopaminergic Neurons, Female, Humans, Inosine, Lewy Body Disease, Male, PTB-Associated Splicing Factor, Parkinson Disease, RNA Editing, RNA, Messenger, RNA-Binding Proteins, alpha-Synuclein
Adenosine, Adenosine Deaminase, Aged, Aged, 80 and over, Cell Nucleus, Dopaminergic Neurons, Female, Humans, Inosine, Lewy Body Disease, Male, PTB-Associated Splicing Factor, Parkinson Disease, RNA Editing, RNA, Messenger, RNA-Binding Proteins, alpha-Synuclein
Neuron
Date: Aug. 07, 2024
PubMed ID: 38761794
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