Disease-specific Induced Pluripotent Stem Cell Modeling: Insights into the Pathophysiology of Valosin Containing Protein (VCP) Disease

Abstract

Valosin Containing Protein (VCP) disease is an autosomal dominant disorder caused by mutations in the VCP gene and is associated with progressive muscle weakness and atrophy. Affected individuals exhibit striking scapular winging due to shoulder girdle weakness. Currently, there are no treatments available and patients are dying early from cardiac and respiratory failure, typically in their 40's and 50's. The generation of disease-specific induced pluripotent stem cells (iPSC) offers a novel platform to investigate mechanisms of VCP disease and potential treatments similar to other disease models including Amyotrophic Lateral Sclerosis (ALS), Duchenne muscular dystrophy (DMD), Parkinson's disease (PD), Alzheimer's disease (AD), Best Disease (BD), and type I juvenile diabetes mellitus (T1DM). Herein, we report the generation and characterization of a human iPSC line to examine the cellular and molecular processes underlying VCP disease. The VCP iPSC line expressed specific pluripotency markers NANOG, SSEA4, OCT-4, TRA-1-81 and exhibited characteristic morphology. We differentiated the human iPSC cell line into a neuronal lineage confirmed by TUJ-1 staining, a neuronal class III β-tubulin marker. We detected higher protein expression levels of ubiquitin (Ub), TAR DNA-binding protein-43 (TDP-43), Light Chain 3-I/II (LC3), p62/SQSTM1, and optineurin (OPN) in the iPSC neural lineage compared to the control neural line. Collectively, our results demonstrate that patient-specific iPSC technology may provide useful disease modeling for understanding the complex mechanisms and for developing novel treatments of VCP and related disorders.

ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

“…Induced pluripotent stem cell (iPSC) -derived motor neuron models of p97 disease have heterogenous phenotypes as well. Initial studies utilizing iPSC-derived motor neurons from a patient with the R155H mutation found increased levels of TDP-43, ubiquitin, and autophagy-related proteins in whole cell lysate 27 . Patani and colleagues refined this phenotype finding TDP-43 mislocalization, ER stress induction, and mitochondrial dysfunction in motor neurons from patients carrying the R155C and R191Q mutations 28 .…”