Font Size:
Site Colors:
S - Skip navigation
1 - Home page
4 - Search
Accessibility Statement

Molecular modifiers of ALS-related mutant FUS aggregation

Amyotrophic lateral sclerosis, ALS, is a neurodegenerative disease with no cure or treatment, leading to gradual paralysis and death within a few years of onset. Mutations in diverse genes have been implicated in the familiar form of the disease, many of which are in RNA binding proteins (RBPs). One common hallmark to the disease, as well as to other neurodegenerative diseases, is the accumulation of protein aggregates within affected neurons.Therefore, targeting the process of aggregation in the disease, and slowing it down, is of major therapeutic potential.

Here we suggest to target the process of aggregation, and perform genome-wide and high-throughput discovery of inhibitors of aggregation. We focus on the ALS-related mutant protein FUS, an RBP which is relatively unexplored in this aspect. We propose two major strategies to identify modifiers of FUS aggregation: (1) protein modifiers, using genome-wide CRISPR and overexpression screens, and (2) RNA modifiers – a completely novel

strategy in this context. Importantly, as our preliminary data shows, our screening approach has already unraveled several factors providing substantial protection of mutant FUS aggregation. Additionally, we have shown that in one case, aggregation of mutant FUS was significantly alleviated in primary neurons.

Our approach would pinpoint multiple targets for future therapy, while also contributing to the understanding of the underlying pathways and processes affected in the disease. While delivery of RNA molecules shows great results in diseases such as SMA, the potential discovery of RNA modifiers relevant to ALS would hold great promise for future therapy.

Confirm and pay