SERCA Silencing Alleviates Aß_(1-42)-Induced Toxicity in a C. elegans Model

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Cellular calcium (Ca2+) homeostasis is crucial for physiological functions.
• Dysregulated Ca2+ signaling is implicated in Alzheimer's Disease (AD) pathogenesis.
• Sarco Endoplasmic Reticulum Ca2+-ATPase (SERCA) plays a key role in maintaining Ca2+ gradients.

Purpose of the Study:

• To investigate the role of SERCA (sca-1) in modulating beta-amyloid (Aß(1-42))-induced muscle dysfunction in a C. elegans model of AD.
• To elucidate the cellular mechanisms underlying SERCA's influence on Aß toxicity.

Main Methods:

• Utilized a C. elegans strain overexpressing human Aß(1-42) in body-wall muscle.
• Employed RNA interference (RNAi) to knockdown the C. elegans SERCA gene (sca-1).
• Assessed worm locomotion, pharyngeal pumping, mitochondrial function (respiration, ROS production), Aß aggregate load, and cytosolic Ca2+ transients.

Main Results:

• sca-1 knockdown significantly improved locomotion and pharyngeal pumping in Aß(1-42) expressing worms.
• sca-1 silencing partially rescued mitochondrial dysfunction, reducing ROS production and restoring mitochondrial organization.
• Reduced Aß aggregate size and number, and prevented oligomer formation were observed upon sca-1 knockdown.
• sca-1 knockdown partially restored altered spontaneous cytosolic Ca2+ transient kinetics.

Conclusions:

• Partial loss of function in SERCA (sca-1) ameliorates Aß(1-42)-induced toxicity in C. elegans muscle.
• This protective effect is mediated by reduced Aß oligomerization and improved mitochondrial function.
• The mechanism involves remodeling of Ca2+ dynamics and partial endoplasmic reticulum Ca2+ depletion.