Targeting Mitochondria in ALS: Divide Less and Conquer?

Striking a balance? Restoring mitochondrial dynamics, by blocking the hyperactivation of the fission regulator Drp1, may help protect motor neurons in ALS by reducing oxidative stress and increasing energy levels, including at the nerve terminals [Courtesy of Joshi et al., 2018, EMBO Molecular Medicine. CC BY 4.0 license.]

Mitochondria malfunction in ALS, potentially contributing to motor neuron destruction. But how to keep energy levels up in motor neurons remains hotly debated (see July 2017 news).

A growing number of preclinical studies suggest that a disruption in the dynamics of mitochondria may contribute to ALS (Magrané et al., 2009; Magrané et al, 2012; Magrane et al., 2014). And, therefore, restoring the balance between fusion and fission of these cellular powerhouses may help transport them along axons, including to the nerve terminals (Song et al., 2013; Wang et al., 2013).

Now, a research team led by Stanford University School of Medicine’s Daria Mochly-Rosen in California report that reducing excess mitochondrial fission may protect motor neurons against ALS – at least in a mouse model of the disease. The study found that sustained treatment with a peptide inhibitor of the activated fission regulator Drp1, after symptom onset (day 90) significantly reduced muscle atrophy, improved motor function and increased survival of G93A SOD1 mice.

The results build on previous studies from the Stanford team which found that the approach reduced neuron loss in mouse models of Huntington’s and Parkinson’s disease (Guo et al., 2013; Qi et al., 2013).

A stress reducer? Reducing excess mitochondrial fission with the treatment of the Dpr1 antagonist P110 improved the survival of G93A SOD1 mice (vehicle: 122 ± 2 days, n = 7; P110: 132 ± 2 days, n = 14). The approach is now being developed by Mitochonix Bio in Israel.[Courtesy of Joshi et al., 2018, EMBO Molecular Medicine. CC BY 4.0 license.]

The approach is based on previous studies, which suggest that increased fragmentation of mitochondria, due to increased fission, contributes to neurological diseases including ALS (for review, see Gao et al., 2017).

The findings suggest that restoring mitochondrial dynamics in neurons may be a potential strategy to treat at least some neurological diseases.

The study appeared on January 15 in EMBO Molecular Medicine.

Meanwhile, University of Iowa’s Stefan Strack is developing a similar strategy in hopes to protect neurons against peripheral diabetic neuropathy (see December 2017 conference news). The small molecule-based strategy, which is being developed in partnership with GlaxoSmithKline, is ongoing. Stay tuned.

***

To learn more about the emerging role of mitochondria in ALS and the challenges targeting them, check out Powering Ahead Targeting Mitochondria in ALS.

Featured Paper

Joshi AU, Saw NL, Vogel H, Cunnigham AD, Shamloo M, Mochly-Rosen D. Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol Med. 2018 Jan 15. pii: e8166. [PubMed].

References

Magrané J, Cortez C, Gan WB, Manfredi G. Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet. 2014 Mar 15;23(6):1413-24. [PubMed].

Magrané J, Sahawneh MA, Przedborski S, Estévez ÁG, Manfredi G. Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci. 2012 Jan 4;32(1):229-42. [PubMed].

Magrané J, Hervias I, Henning MS, Damiano M, Kawamata H, Manfredi G. Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Hum Mol Genet. 2009 Dec 1;18(23):4552-64. [PubMed].

Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E. Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1α. Neurobiol Dis. 2013 Mar;51:72-81. [PubMed].

Wang W, Li L, Lin WL, Dickson DW, Petrucelli L, Zhang T, Wang X. The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet. 2013 Dec 1;22(23):4706-19. [PubMed].

Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D, Qi X. Inhibition of mitochondrial fragmentation diminishes Huntington’s disease-associated neurodegeneration. J Clin Invest. 2013 Dec;123(12):5371-88. [PubMed].

Qi X, Qvit N, Su YC, Mochly-Rosen D. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci. 2013 Feb 1;126(Pt 3):789-802. [PubMed].

Further Reading

Gao J, Wang L, Liu J, Xie F, Su B, Wang X. Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases. Antioxidants (Basel). 2017 Apr 5;6(2). [PubMed].

***

This is an updated version of this article. The report was originally posted on December 5, as part of our coverage of the 2017 Annual Meeting of the Society of Neuroscience.

disease-als mitochondria mitochondrial dynamics mitochondrial fission mitochondrial fusion neuroprotection P110 topic-preclinical topic-randd
Share this:
Facebooktwittergoogle_plusmailFacebooktwittergoogle_plusmail