Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects cells in the brain and the spinal cord. This devastating, fatal ailment afflicts about 15,000 Americans at any given time. No cure is available for ALS, and available treatments fail to control symptoms. Owing to this, there is an urgent need for conceptually novel therapies capable of rapidly and safely treating patients suffering from ALS. Our long-term objective is to understand the role of epigenetic mechanisms in the etiology of neurodegenerative disease. The central hypothesis of our research is that posttranslational modification (PTM) of histones has a role in cellular demise in ALS. Epigenetics may reveal a mechanism behind the occurrence of disease, serving as the missing link between genetic and environmental factors. We will pursue these studies in two specific aims: Phase I Specific Aim 1: Determine the Genome-Wide Post-translational Modification of Histones in ALS In this aim, we will explore the global epigenetic make up of both yeast over expressing FUS and TDP- 43 and induced pluripotent stem cells (iPS) from ALS patients and their respective controls through western blotting and mass spectrometry (MS) proteomics. The proposed work is innovative, because it explores an understudied area in the biology of ALS. Furthermore, this project utilizes modern techniques to solve questions inaccessible through conventional biochemical experiments. Our working hypothesis for this aim is that changes on histone PTMs are associated with the cytotoxic protein aggregation seen in ALS. Phase II Specific Aim 2: Explore Chemical Interventions that Lessen ALS Cytotoxicity In an independent approach, we will identify small molecules targeting epigenetic mechanisms that are able to reduce cytotoxicity in ALS iPS cells. Furthermore, I will investigate the details of the mechanisms behind these effects. At the completion of this project, we expect that the combination of work proposed in aims 1 and 2 will uncover novel epigenetic mechanisms at play in the context of cytotoxic protein aggregation. These mechanisms are highly accessible targets for pharmaceutical treatments and thus they can open the door to new, alternative strategies in the treatment of ALS and other neurodegenerative diseases.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects cells in the brain and the spinal cord. No cure is available for ALS, and available treatments fail to control symptoms. Genetics alone is unable to explain why this disease occurs. We plan to study the role of epigenetics in the origins of ALS. Epigenetics studies traits that are inherited without changes in our genes. The results of this study will reveal novel information about ALS and will hopefully open the door to a new, more effective generation of treatments for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K22)
Project #
5K22NS091314-03
Application #
9223674
Study Section
NST-1 Subcommittee (NST-1)
Program Officer
Gubitz, Amelie
Project Start
2015-09-15
Project End
2018-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2016
Total Cost
$153,370
Indirect Cost
$11,361
Name
Brooklyn College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
620127691
City
New York
State
NY
Country
United States
Zip Code
11210
Chen, Karen; Bennett, Seth A; Rana, Navin et al. (2018) Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post-translational Modification Landscapes. ACS Chem Neurosci 9:838-848
Bennett, Seth A; Tanaz, Royena; Cobos, Samantha N et al. (2018) Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease. Transl Res :
Tariq, Amber; Lin, JiaBei; Noll, Megan M et al. (2018) Potentiating Hsp104 activity via phosphomimetic mutations in the middle domain. FEMS Yeast Res 18:
Cobos, Samantha N; Bennett, Seth A; Torrente, Mariana P (2018) The impact of histone post-translational modifications in neurodegenerative diseases. Biochim Biophys Acta Mol Basis Dis :
Gates, Stephanie N; Yokom, Adam L; Lin, JiaBei et al. (2017) Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Science 357:273-279
Torrente, Mariana P; Chuang, Edward; Noll, Megan M et al. (2016) Mechanistic Insights into Hsp104 Potentiation. J Biol Chem 291:5101-15