Journal
FASEB JOURNAL
Volume 35, Issue 7, Pages -Publisher
WILEY
DOI: 10.1096/fj.202100137R
Keywords
amyotrophic lateral sclerosis (ALS); ER-mitochondria contact; mitochondria-associated membrane (MAM); organelle; sigma-1 receptor (Sig1R)
Categories
Funding
- Japan Agency for Medical Research and Development (AMED) [21ek0109426h0002]
- Uehara Memorial Foundation
- Public Foundation of Chubu Science and Technology Center
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The study found that MAM disruption is a common pathological feature in ALS, but there is currently a lack of simple and effective tools for monitoring the status of MAM. Scientists have developed two new MAM reporter genes that can monitor the effects of various ALS-causative genes on MAM.
The mitochondria-associated membrane (MAM) is a functional subdomain of the endoplasmic reticulum membrane that tethers to the mitochondrial outer membrane and is essential for cellular homeostasis. A defect in MAM is involved in various neurological diseases, including amyotrophic lateral sclerosis (ALS). Recently, we and others reported that MAM was disrupted in the models expressing several ALS-linked genes, including SOD1, SIGMAR1, VAPB, TARDBP, and FUS, suggesting that MAM disruption is deeply involved in the pathomechanism of ALS. However, it is still uncertain whether MAM disruption is a common pathology in ALS, mainly due to the absence of a simple, quantitative tool for monitoring the status of MAM. In this study, to examine the effects of various ALS-causative genes on MAM, we created the following two novel MAM reporters: MAMtracker-Luc and MAMtracker-Green. The MAMtrackers could detect MAM disruption caused by suppression of SIGMAR1 or the overexpression of ALS-linked mutant SOD1 in living cells. Moreover, the MAMtrackers have an advantage in their ability to monitor reversible changes in the MAM status induced by nutritional conditions. We used the MAMtrackers with an expression plasmid library of ALS-causative genes and noted that 76% (16/21) of the genes altered MAM integrity. Our results suggest that MAM disruption is a common pathological feature in ALS. Furthermore, we anticipate our MAMtrackers, which are suitable for high-throughput assays, to be valuable tools to understand MAM dynamics.
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