Transient contact sites between mitochondrial and ER membranes, called mitochondria-associated ER membranes (MAMs), play an important role in cellular homeostasis, calcium signaling, and mitochondrial function. The ALS-linked proteins VAPB and TDP-43 can perturb these structures and lead to mitochondrial dysfunction (see July 2014 news). Results published November 7 online in EMBO Molecular Medicine link two more ALS-linked proteins to MAM disruption: mutant SOD1 (mSOD1) and the sigma 1 receptor (Sig1R). These proteins were enriched at the MAM, and in both Sig1R null and SOD1-ALS mice the MAMs collapsed. This resulted in dispersion of the inositol triphosphate receptor type-3 (IP3R3), which is normally concentrated at motor neuron MAMs and interacts with wild-type Sig1R to regulate calcium signaling. These findings suggest that loss of MAM integrity may be a convergent mechanism underlying multiple forms of ALS.
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Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, Kiyama H, Yamanaka K. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med. 2016 Nov 7. [Pubmed].