S1R-E102Q variant induces S1R accumulation and increases in FUS expression in hippocampal neurons. (a) Primary rat neuronal culture transfected with S1R-WT and S1R-E102Q plasmid DNA carrying the V5 tag. ALS FUS marker expression is shown in magenta and S1R-WT
and S1R-E102Q protein are shown in green. (b) Graphical representation of S1R (WT an E102Q) and FUS expression in neurons.
Project description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and characterized by the loss of motor functions. The autosomal recessive mutation c.304G>C (p.E102Q) in the SIGMAR1 gene is known to cause the development of juvenile ALS in humans. Furthermore, this rare form of the disease is responsible for 5-10% of ALS patients (www.als.org). The chaperone protein Sigma-1R (S1R) has various regulatory functions and interacts with the potassium channel Kv1.2. This interaction is known to influence neuronal excitability (Kourrich, 2017.) Indeed, to maintain a tight regulation of neuronal excitability, voltage-gated potassium channels (Kvs) must be regulated and transported properly to the plasma membrane. My research hypothesis suggests that the E102Q variant disturbs Kv1.2 channel trafficking to the plasma membrane and inhibits S1R functions in regulating neuronal excitability, and thus, contributes to the development of ALS. Using a translational approach, my project consists in studying the interaction between the S1R-E102Q variant and Kv1.2 channel, determining its impact on the plasma membrane trafficking of Kv1.2, as well as on the locomotor functions of mice using several behavioral tasks.
Research team
Name: Sara-Maude Bélanger, BSc
Supervisor: Saïd Kourrich (UQAM)
Laureate: Master scholarship 2022