Compromised paraspeckle formation as a pathogenic factor in FUSopathies

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• Paraspeckles are nuclear bodies regulating RNA processing and stress responses.
• Fused in sarcoma (FUS) protein is essential for paraspeckle assembly and is implicated in neurodegenerative disorders.

Purpose of the Study:

• To investigate the role of FUS in paraspeckle formation and function.
• To determine how FUS mutations affect paraspeckle integrity and contribute to FUSopathies.

Main Methods:

• Studied FUS recruitment to paraspeckles via its N-terminal region and prion-like activity.
• Analyzed FUS interaction with p54nrb/NONO in an RNA-dependent manner.
• Assessed the impact of FUS deficiency and mutations on paraspeckle formation and cellular homeostasis.

Main Results:

• FUS recruitment to paraspeckles requires its N-terminal region and prion-like activity.
• FUS regulates NEAT1 levels and paraspeckle formation; FUS deficiency causes paraspeckle loss.
• ALS-linked FUS mutations lead to paraspeckle protein aggregation and neuronal inclusions in patients.

Conclusions:

• Both loss and gain of FUS function disrupt paraspeckle assembly.
• Impaired paraspeckle function may contribute to neuronal dysfunction and pathogenesis in FUSopathies, including ALS.