Mitochondrial Membrane Collapse Associated With ALS

The disruption of the mitochondria-associated membrane is an indicator of amyotrophic lateral sclerosis, researchers say.

AsianScientist (Nov. 16, 2016) – Two distinct forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) are linked by defects in the mitochondrial membrane, according to research published in EMBO Molecular Medicine.

ALS is an adult onset muscle wasting disease that currently has no cure. To date, more than 20 genes have been identified as a causes of inherited ALS, and many researchers are investigating the mechanism of the disease.

Focusing on the mitochondria-associated membrane (MAM) where the mitochondria meets the endoplasmic reticulum, researchers led by Professor Koji Yamanaka at Nagoya University found that the collapse of the membrane is a common pathological hallmark in both SIGMAR1- and SOD1-linked ALS.

In patients with mutated SIGMAR1, the mutant proteins were unstable and non-functional, causing a disruption in MAM. To address the question of whether disrupted MAM are also involved in other ALS cases, the researchers cross-bred SIGMAR1-deficient mice with mice which overexpress a mutant form of SOD1 gene and show symptoms similar to ALS.

They found that SIGMAR1 deficiency accelerated disease onset in SOD1-ALS mice by more than 20 percent. In those mice, inositol triphosphate receptor type-3 (IP3R3), a MAM-enriched calcium ion (Ca2+) channel on ER, disappeared from the MAM. The loss of proper localization of IP3R3 led to Ca2+ dysregulation that worsened neurodegeneration.

These results suggest that preventing MAM disruption could be used to treat ALS patients. The researchers noted that the collapse of MAM is widely observed in the other genetic causes of ALS, and conclude that their findings may be applicable to sporadic ALS patients.

The article can be found at: Watanabe et al. (2016) Collapse of Mitochondria-associated Membrane is a Common Pathomechanism in SIGMAR1- and SOD1-linked ALS.


Source: Nagoya University; Photo: Koji Yamanaka Laboratory.
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