Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases. Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression. However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions. Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.

Errataetall:

CommentIn: Nature. 2017 Apr 20;544(7650):302-303. - PMID 28405020

Medienart:

E-Artikel

Erscheinungsjahr:

2017

Erschienen:

2017

Enthalten in:

Zur Gesamtaufnahme - volume:544

Enthalten in:

Nature - 544(2017), 7650 vom: 20. Apr., Seite 367-371

Sprache:

Englisch

Beteiligte Personen:

Becker, Lindsay A [VerfasserIn]
Huang, Brenda [VerfasserIn]
Bieri, Gregor [VerfasserIn]
Ma, Rosanna [VerfasserIn]
Knowles, David A [VerfasserIn]
Jafar-Nejad, Paymaan [VerfasserIn]
Messing, James [VerfasserIn]
Kim, Hong Joo [VerfasserIn]
Soriano, Armand [VerfasserIn]
Auburger, Georg [VerfasserIn]
Pulst, Stefan M [VerfasserIn]
Taylor, J Paul [VerfasserIn]
Rigo, Frank [VerfasserIn]
Gitler, Aaron D [VerfasserIn]

Links:

Volltext

Themen:

Ataxin-2
DNA-Binding Proteins
Journal Article
Oligonucleotides, Antisense
TARDBP protein, human

Anmerkungen:

Date Completed 22.08.2017

Date Revised 27.03.2024

published: Print-Electronic

CommentIn: Nature. 2017 Apr 20;544(7650):302-303. - PMID 28405020

Citation Status MEDLINE

doi:

10.1038/nature22038

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM270923136