Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Motor neuron disease (MND) is a progressive neurodegenerative disorder lacking effective treatments.
• Cytoplasmic inclusions of TAR DNA binding protein 43 (TDP-43) are a key pathological hallmark of MND.
• The precise mechanisms driving endogenous TDP-43 aggregation in MND remain unclear.

Purpose of the Study:

• To investigate the induction of endogenous TDP-43 cytoplasmic accumulation in a motor neuronal cell line.
• To elucidate the role of endoplasmic reticulum (ER) stress in TDP-43 aggregation.
• To determine the involvement of casein kinase 1 (CK1) in ER stress-induced TDP-43 pathology.

Main Methods:

• Utilized the NSC-34 motor neuronal cell line.
• Induced ER stress using the agent tunicamycin.
• Employed immunocytochemistry and immunoblotting to detect TDP-43 and phosphorylated TDP-43.
• Assessed the impact of CK1 inhibition on TDP-43 accumulation.

Main Results:

• Tunicamycin-induced ER stress led to CK1-dependent cytoplasmic accumulation of endogenous TDP-43.
• ER stress increased TDP-43 and phosphorylated TDP-43 in the NP-40/RIPA-insoluble fraction.
• CK1 inhibition significantly reduced these increases in TDP-43 aggregation.
• High molecular weight TDP-43 species were observed in the insoluble fraction.

Conclusions:

• ER stress signaling, exemplified by tunicamycin treatment, promotes TDP-43 phosphorylation.
• This phosphorylation event is mediated by CK1 and results in TDP-43 cytosolic accumulation.
• These findings highlight a novel pathway linking ER stress to TDP-43 pathology in motor neuron disease.