Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology.

Reichenstein, Irit; Eitan, Chen; Diaz-Garcia, Sandra; Haim, Guy; Magen, Iddo; Siany, Aviad; Hoye, Mariah L; Rivkin, Natali; Olender, Tsviya; Toth, Beata; Ravid, Revital; Mandelbaum, Amitai D; Yanowski, Eran; Liang, Jing; Rymer, Jeffrey K; Levy, Rivka; Beck, Gilad; Ainbinder, Elena; Farhan, Sali M K; Lennox, Kimberly A; ... (2019). Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology. Science translational medicine, 11(523) American Association for the Advancement of Science 10.1126/scitranslmed.aav5264

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Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Sahli Building > Forschungsgruppe Neurologie

UniBE Contributor:

Saxena, Smita

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1946-6234

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Chantal Kottler

Date Deposited:

16 Jan 2020 16:00

Last Modified:

19 Jan 2020 02:49

Publisher DOI:

10.1126/scitranslmed.aav5264

PubMed ID:

31852800

BORIS DOI:

10.7892/boris.137733

URI:

https://boris.unibe.ch/id/eprint/137733

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