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Published on: March 24, 2019
Yeast Models of Amyotrophic Lateral Sclerosis Type 8 Mimic Phenotypes Seen in Mammalian Cells Expressing Mutant
AnnaMari L Stump1,2, Daniel J Rioux1,2, Richard Albright1
1Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that results in the loss of motor neurons and can occur sporadically or due to genetic mutations. Among the 30 genes linked to familial ALS, a P56S mutation in VAPB, an ER-resident protein that functions at membrane contact sites, causes ALS type 8. Mammalian cells expressing VAPBP56S have distinctive phenotypes, including ER collapse, protein and/or membrane-containing inclusions, and sensitivity to ER stress. VAPB is conserved through evolution and has two homologs in budding yeast, SCS2 and SCS22. Previously, a humanized version of SCS2 bearing disease-linked mutations was described, and it caused Scs2-containing inclusions when overexpressed in yeast. Here, we describe a yeast model for ALS8 in which the two SCS genes are deleted and replaced with a single chromosomal copy of either wild-type or mutant yeast SCS2 or human VAPB expressed from the SCS2 promoter. These cells display ER collapse, the formation of inclusion-like structures, and sensitivity to tunicamycin, an ER stress-inducing drug. Based on the phenotypic similarity to mammalian cells expressing VAPBP56S, we propose that these models can be used to study the molecular basis of cell death or dysfunction in ALS8. Moreover, other conserved ALS-linked genes may create opportunities for the generation of yeast models of disease.
Insights
Researchers developed a new yeast model for Amyotrophic Lateral Sclerosis type 8 (ALS8). This model mimics key disease features, offering a valuable tool to study ALS8's molecular mechanisms and potential treatments.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease impacting motor neurons, with genetic factors playing a role in familial cases.
- A specific mutation (P56S) in the VAPB gene causes ALS type 8, leading to cellular stress and dysfunction in mammalian cells.
- VAPB has conserved homologs (SCS2, SCS22) in yeast, suggesting conserved biological functions.
Purpose of the Study:
- To create a novel yeast model for studying ALS type 8 (ALS8).
- To investigate the cellular phenotypes associated with VAPB mutations in a simplified model system.
- To establish a platform for exploring the molecular basis of ALS8 pathogenesis.
Main Methods:
- Deletion of yeast SCS2 and SCS22 genes.
- Introduction of a single chromosomal copy of wild-type or mutant yeast SCS2, or human VAPB, into the deleted locus.
- Phenotypic analysis including endoplasmic reticulum (ER) morphology, inclusion formation, and sensitivity to ER stress agents like tunicamycin.
Main Results:
- The engineered yeast cells exhibited ER collapse, a hallmark of VAPB(P56S) expression in mammalian cells.
- Formation of inclusion-like structures was observed in the yeast models.
- The yeast models demonstrated increased sensitivity to tunicamycin, indicating ER stress.
Conclusions:
- The developed yeast model accurately recapitulates key cellular phenotypes of ALS8 observed in mammalian cells.
- This model provides a powerful tool for dissecting the molecular mechanisms underlying VAPB-linked ALS.
- The conserved nature of ALS-associated genes suggests the potential for generating similar yeast models for other forms of ALS.
