Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Tau aggregates are implicated in neurodegenerative diseases such as Alzheimer's disease (AD).
• RNA is known to promote tau aggregation in vitro, but its presence within cellular tau aggregates was unconfirmed.
• Understanding the molecular composition of tau aggregates is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To investigate whether tau aggregates within cells contain RNA.
• To determine the types of RNA associated with tau aggregates.
• To explore the functional consequences of RNA in tau aggregates on cellular processes, particularly pre-mRNA splicing.

Main Methods:

• Utilized cell culture and mouse brain models to examine tau aggregates.
• Employed techniques to identify and characterize RNA within cytosolic and nuclear tau aggregates.
• Investigated the colocalization and impact of tau aggregates on nuclear speckles and their components.
• Analyzed alterations in pre-mRNA splicing in the presence of tau aggregates.

Main Results:

• Demonstrated that both cytosolic and nuclear tau aggregates contain RNA, with a notable enrichment of small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs).
• Showed that nuclear tau aggregates interact with nuclear speckles, altering their composition, dynamics, and organization.
• Observed mislocalization of nuclear speckle components, such as SRRM2, to cytosolic tau aggregates in various tauopathies, including AD, frontotemporal dementia (FTD), and corticobasal degeneration (CBD).
• Confirmed that tau aggregates are sufficient to induce changes in pre-mRNA splicing.

Conclusions:

• Tau aggregates sequester RNA, including snRNAs and snoRNAs, within cells.
• Tau aggregation disrupts the normal function and organization of nuclear speckles, key sites for pre-mRNA splicing.
• The mislocalization of nuclear speckle components to tau aggregates and subsequent alteration of splicing represent a novel pathogenic mechanism in tauopathies.
• This finding provides a potential link between tau pathology and aberrant RNA processing in neurodegenerative diseases.