Karakteriseren van mutaties in hnRNPA2 voor de identificatie van pathogene mechanismen in degeneratieve disorders

Heterogeneous ribonucleoprotein (hnRNP) A2/B1 is a protein
involved in RNA maturation and mRNA transport. Recently, it has
been shown to undergo liquid-liquid phase separation (LLPS), a
process where a biomolecule forms liquid droplets in solutions. In
cells, LLPS allows the cell to rapidly respond to environmental
conditions such as the cellular stress response. However,
misregulation of LLPS has been linked to the accumulation of
pathogenic aggregates. Mutations in hnRNPA2 have been related to
amyotrophic lateral sclerosis (ALS), multisystem proteinopathy
(MSP), and Paget’s disease of the bone (PDB). Although diseaselinked mutations have been shown to increase the aggregation
propensity of proteins, the potential pathogenic alterations on phase
separation remain undiscovered. During my Ph.D., I will study
hnRNPA2 and its two disease-associated mutants (D290V and
P298L) as a case study for LLPS in vitro, and in cellular models. I
expect to identify differences in LLPS propensity and droplet
properties among wild-type and mutant hnRNPA2. I will also study
the transition from droplets to aggregates to define the location
where aggregation begins. I will complement these results with
cellular experiments, where the first cellular characterization of the
P298L mutant will be performed. Together, these results will provide
insights into the effect(s) of mutations on the phase separation and
subsequent aggregation of hnRNPA2 and will shed light on the
possible disease mechanisms