Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 and FUS are RNA-binding proteins implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
• Cytoplasmic inclusions of TDP-43 and FUS are pathological hallmarks in ALS and FTLD.
• The precise mechanisms underlying TDP-43 and FUS aggregation and toxicity remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms of FUS aggregation and toxicity using a yeast model and purified FUS.
• To compare the aggregation and toxicity mechanisms of FUS with those of TDP-43.
• To identify genetic factors influencing FUS and TDP-43 toxicity.

Main Methods:

• Utilized a yeast model system to study FUS aggregation and toxicity.
• Employed purified FUS protein to investigate spontaneous aggregation.
• Conducted genome-wide screens to identify genetic modifiers of FUS and TDP-43 toxicity.

Main Results:

• FUS aggregation in the cytoplasm and RNA binding are essential for toxicity in yeast, similar to TDP-43.
• FUS aggregates localize to stress granules, mirroring observations in ALS patients.
• FUS aggregation requires a prion-like domain and specific RGG domain determinants, distinct from TDP-43.
• ALS-linked FUS mutations do not enhance aggregation, unlike some TDP-43 mutations.
• Genetic screens identified distinct sets of genes modifying FUS and TDP-43 toxicity, particularly related to stress granule assembly and RNA metabolism.

Conclusions:

• TDP-43 and FUS, despite being similar RNA-binding proteins, aggregate and cause disease through distinct mechanisms.
• FUS aggregation is influenced by specific domains and genetic factors differently than TDP-43.
• These mechanistic differences highlight the need for distinct therapeutic strategies for ALS/FTLD patients with TDP-43 or FUS pathology.