Novel therapeutic targets for amyotrophic lateral sclerosis: ribonucleoproteins and cellular autonomy

ABSTRACT

Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating disease with a lifetime risk of approximately 1:400. It is incurable and invariably fatal. Average survival is between 3 and 5 years and patients become increasingly paralyzed, losing the ability to speak, eat, and breathe. Therapies in development either (i) target specific familial forms of ALS (comprising a minority of around 10% of cases) or ii) emanate from (over)reliance on animal models or non-human/non-neuronal cell models. There is a desperate and unmet clinical need for effective treatments. Deciphering the primacy and relative contributions of defective protein homeostasis and RNA metabolism in ALS across different model systems will facilitate the identification of putative therapeutic targets.

Areas covered

This review examines the putative common primary molecular events that lead to ALS pathogenesis. We focus on deregulated RNA metabolism, protein mislocalization/pathological aggregation and the role of glia in ALS-related motor neuron degeneration. Finally, we describe promising targets for therapeutic evaluation.

Expert opinion

Moving forward, an effective strategy could be achieved by a poly-therapeutic approach which targets both deregulated RNA metabolism and protein dyshomeostasis in the relevant cell types, at the appropriate phase of disease.

KEYWORDS:

• Amyotrophic lateral sclerosis (ALS)
• splicing
• intron retention
• protein aggregation
• oligomer
• astrocyte
• motor neuron
• reactive transformation

Article highlights

• ALS is a devastating neurodegenerative disease in which further investigation of molecular and cellular events is crucial to elucidate therapeutically targetable mechanisms.

• Aberrant splicing (including intron retention) and nuclear loss of RNA binding proteins (RBPs) are observed in ALS.

• Protein misfolding (including toxic oligomerization) underlies ALS pathogenesis to some degree, including aggregation and a prion-like cell-to-cell propagation.

• Astrocytes and microglia undergo deleterious reactive transformation in ALS, which perturbs their neuroprotective capacity.

• Elucidation of primary pathogenic events in motor neurons and glia through integration of different ALS models is crucial and will allow the identification of high confidence therapeutic targets.

• Considering a poly-therapeutic approach will likely advance our efforts in ultimately discovering the most effective therapeutic strategies.

This box summarizes key points contained in the article.

Acknowledgments

The work of the authors is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK 65 (FC010110), the UK Medical Research Council (FC010110), and the Wellcome Trust (FC010110). R.P. holds an MRC Senior Clinical Fellowship [MR/S006591/1].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

R.P. holds an MRC Senior Clinical Fellowship [MR/S006591/1]. The work of the authors is also supported by the Francis Crick Institute which receives its core funding from Cancer Research UK 65 (FC010110), the UK Medical Research Council (FC010110), and the Wellcome Trust (FC010110).