MicroRNA May Be To Blame For Loss of Key Support Network in Motor Neurons In ALS

Astrocytes fuel the progression of ALS. But how these neuronal support cells contribute to the disease remains hotly debated.

Pulling the plug? Astrocytes may contribute to at least some forms of ALS by failing to support them (see August 2014, August 2017 news).[Courtesy of Hall et al., 2017, Cell Reports]

Astrocytes may destroy motor neurons by secreting toxic substances (see August 2011 news, October 2011 news, January 2017 news, February 2017 news). But according to a growing number of studies, astrocytes might contribute to at least some forms of ALS by simply withdrawing their support of motor neurons during a time of great need (see August 2017 news; see also August 2014 news on Kwon et al., 2014).

Now, a research team led by Timothy Miller at Washington University School of Medicine in St Louis, Missouri report that astrocytes may lose the ability to soak up excess glutamate in motor neurons in ALS by a microRNA-based mechanism (Hoye et al., 2018).

The study found that the microRNA miR-216, released by degenerating motor neurons, is taken up by astrocytes and reduces the expression of the glutamate transporter EAAT2.

The results build on a previous preclinical study from the Washington University team which found that miR-216 is enriched in motor neurons and is released upon injury and/or decline (Hoye et al., 2017).

The study appeared on July 10 in Brain.

Meanwhile, scientists at Biogen in Cambridge, MA and Ionis Pharmaceuticals in Carlsbad, California, in collaboration with Miller’s team, are developing a potential therapy for SOD1 ALS (see July 2018 news; McCampbell et al., 2018). The approach also reduces levels of miR-216 which is released at about disease onset – at least in ALS model mice (Hoye et al., 2017). The strategy is currently at the phase 1 stage (see May 2018 conference news).

References

Hoye ML, Regan MR, Jensen LA, Lake AM, Reddy LV, Vidensky S, Richard JP, Maragakis NJ, Rothstein JD, Dougherty JD, Miller TM. Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis. Brain. 2018 Jul 10. [PubMed].

Hoye ML, Koval ED, Wegener AJ, Hyman TS, Yang C, O’Brien DR, Miller RL, Cole T, Schoch KM, Shen T, Kunikata T, Richard JP, Gutmann DH, Maragakis NJ, Kordasiewicz HB, Dougherty JD, Miller TM. MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models. J Neurosci. 2017 May 31;37(22):5574-5586. [PubMed].

McCampbell A, Cole T, Wegener AJ, Tomassy GS, Setnicka A, Farley BJ, Schoch KM, Hoye ML, Shabsovich M, Sun L, Luo Y, Zhang M, Thankamony S, Salzman DW, Cudkowicz M, Graham DL, Bennett CF, Kordasiewicz HB, Swayze EE, Miller TM. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018 Aug 1;128(8):3558-3567. [PubMed].

Further Reading

Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani R. Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. Cell Rep. 2017 May 30;19(9):1739-1749. [PubMed].

Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, Kim J, Yun J, Xie Y, McKnight SL. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014 Sep 5;345(6201):1139-45. [PubMed].

A1 astrocyte antisense oligonucleotides astrocytes disease-als eaat2 excitotoxicity glutamate microRNA miR-216 non-cell autonomous SOD1 SOD1-Rx
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