Amyotrophic lateral sclerosis (ALS) is a fatal, adult onset, neurodegenerative disease for which there is currently no cure and very limited treatment options. Patients present with increasing muscle weakness and die from respiratory failure within 3-5 years post symptom onset. Currently, the majority of ALS research is focused on genetic causes, which account for approximately only 10% of cases (familial), without any treatment developments for the remaining 90% of patients (sporadic). Although nothing is known about the pathogenesis or propagation of disease, 97% of all patients share one pathological hallmark: TDP-43 mislocalization. TDP-43 is an essential RNA binding protein that in healthy patients is expressed in spinal cord and cortical motor neuron nuclei. In ALS it is mislocalized to the cytoplasm where it forms distinct phosphorylated aggregates which may be toxic to the neurons. Recently, Ataxin-2 (ATXN2) has been identified as a potential modulator of TDP-43 toxicity in yeast and animal models. To support this finding, 5% of patients with ALS have intermediate length repeat expansions in the polyQ region of the gene, compared to 2% of non-neurological controls. Furthermore, our group and others have demonstrated that regardless of repeat length, ALS patients demonstrate perturbations in the distribution of ATXN2 in motor neurons. Taken together, these suggest that ATXN2 may be a candidate for antisense oligonucleotide (ASO) therapeutic potential, however, the question remains as to whether therapy would benefit all sporadic patients or be dependent on polyQ length. This project proposes a series of experiments designed to examine ATXN2 as a potential therapeutic target in human tissue directly from patients with disease, comparing patients with and without intermediate length repeat expansions.
The aims will explore target characterization and phenotype by examining expression levels and pathways involved in disease. The proposal examines target engagement via knocking down levels of ATXN2 and related proteins in the pathway and exploring the changes in genomic and proteomic signature to develop a disease cellular profile. Lastly, it will verify target efficacy with ATXN2-targeted ASO treatment in order to identify the subset of patients likely to benefit from therapy. Due to the devastating nature of ALS it is imperative that research focus on therapeutic potential in a directly translatable manner in order to expedite treatments for current patients. This proposal will stratify the patient population of those likely to benefit from ATXN2 directed therapy, however, the field remains optimistic that removal of ATXN2 will benefit all patients, not just the small percentage of those with intermediate length repeats. This directly translatable proposal, along with monthly patient contact in the largest ALS clinic in San Diego, will provide ideal physician scientist training in a collaborative research and clinical setting.

Public Health Relevance

Ataxin-2 has recently been identified as a promising potential therapeutic target in ALS, a rapidly fatal neurodegenerative disease with no known cause or treatment. However, the mechanism by which ATXN2 functions and how an expanded repeat in the gene is involved in ALS pathogenesis is not known. This proposal aims to examine the biological, neuropathological and therapeutic potential of ATXN2 in ALS and assess target engagement and therapeutic efficacy of ATXN2-targeting ASO therapy in order to determine if targeting ATXN2 may provide a cure for ALS.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Opanashuk, Lisa A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California, San Diego
Schools of Medicine
La Jolla
United States
Zip Code