Modeling Motor Neuron Disease


Pioneer Founding member
10/02/2014 Kelly Rae Chi

In neurons, mitochondria shuttle all the way from the cell body down the length of the axon and back again, providing the cell and its synapses with a constant source of energy. Now researchers have shown that interfering with mitochondrial movement, but not function, in specific populations of neurons is sufficient to cause symptoms reminiscent of motor neuron diseases such as spastic paraplegia and amyotrophic lateral sclerosis in mice.

The results, published in Proceedings of the National Academy of Sciences (1) could inform new strategies for treating neurodegenerative diseases in which the mitochondrial movement and distribution go awry.

Mammalian mitochondrial Rho 1, or Miro1, and its relative Miro2 are mitochondrial surface receptors that attach to microtubule tracks running the length of axons. Although both receptors are involved in transport, no one had yet studied their roles in neuronal development and maintenance in vivo.

In the new study, a team led by Janet Shaw, professor of biochemistry at the University of Utah School of Medicine, created mice missing Miro1. Although mitochondria from these mice appeared normal and were able to respire, generate ATP, and buffer calcium, the mice died immediately after birth due to the absence of motor neurons that control breathing.

Interested in the role of mitochondria in motor neurons, graduate student Tammy Nguyen carefully chose Cre drivers to knock out Miro1 in various specific neural tissues. The resulting mice, missing Miro1 from the cerebral cortex, hippocampus, and spinal cord, lived past birth, but by two weeks of age developed hind-limb clasping, an early sign of neuronal deficit. The animals went on to develop more severe movement defects. “It became clear that it was upper motor neurons that were the problem,” said Shaw.

Shaw’s group is now generating several other mutant mice, one of them an inducible model that will allow them to study Miro1 in the adult brain. They plan to use cells from these mice to screen for drugs that rescue the distribution defect.

They are also creating Miro2-deficient mice. Miro1 and Miro2 are 60% similar in their sequences, but likely have distinct roles. “We’re very interested in knowing what it is Miro2 does that Miro1 doesn’t, and vice versa,” Shaw said.


Nguyen TT, Oh SS, Weaver D, Lewandowska A, Maxfield D, Schuler MH, Smith NK, Macfarlane J, Saunders G, Palmer CA, Debattisti V, Koshiba T, Pulst S, Feldman EL, Hajnóczky G, Shaw JM. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci 2014 Sep 2;111:E3631-40. doi: 10.1073/pnas.1402449111. Epub 2014 Aug 18.