Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Amyotrophic Lateral Sclerosis (ALS) involves motoneuron degeneration.
• Familial ALS (fALS) is linked to mutations in C9orf72, FUS, SOD1, and TARDBP.
• Intrinsically disordered regions (IDRs) in ALS proteins drive liquid-liquid phase separation (LLPS) and stress granule (SG) formation.

Purpose of the Study:

• To investigate the hypothesis that profilin isoforms are sequestered in ALS-associated protein aggregates.
• To determine if this sequestration leads to actin cytoskeleton dysregulation.
• To explore the role of profilins in ALS pathomechanisms.

Main Methods:

• Cellular models of ALS.
• Immunofluorescence microscopy to observe protein localization.
• Analysis of actin dynamics.

Main Results:

• Profilin-2 (PFN2) showed greater localization to SGs than profilin-1 (PFN1).
• FUS and C9orf72 aggregates sequestered PFN2, but not PFN1.
• PFN2 and G-actin were distinctly sequestered in C9orf72 aggregates, leading to dysregulated actin dynamics.

Conclusions:

• Profilin isoforms, particularly PFN2, are implicated in ALS pathogenesis through sequestration in protein aggregates.
• ALS-associated protein aggregates can dysregulate actin dynamics via profilin sequestration.
• Profilins may play a more significant role in ALS than previously suggested by rare mutations.