Development of Clinical Biomarkers for Molecular Subtypes of Sporadic ALS
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a complex disease. Several inherited gene mutations are known to cause ALS. However, for 90% of those living with ALS, they have no close family members with ALS or known gene mutations that caused the disease. Despite this variation in genetic contributions to ALS, several other commonalities have been identified. For example, nearly all patients show accumulations of a protein called TDP-43 in the tissues affected by this disease (brain and spinal cord). Moreover, work from our own laboratories as part of the New York Genome Center (NYGC) ALS Consortium has shown that there are clear patterns of RNA and protein changes that happen in the brain tissues of people with ALS (pALS). Rather than a single pattern of RNA and protein changes for all pALS cases, we have shown that there are three characteristic patterns seen in brain tissues. These three characteristic patterns of RNA and protein changes have been called ALS sub-groups. ALS sub-groups can be defined by whether the brain tissues display signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), activation of pro-inflammatory cells (glia) and neuroinflammation (ALS-Glia), or dense TDP-43 pathology and associated elevation of transposable elements (ALS-TE). Transposable elements are viral-like pieces of our genome that are normally silent, but can become activated in response to stress. The patterns identified in the NYGC ALS patient samples (mitochondrial dysfunction, inflammation, and TDP-43 pathology) have been previously implicated in ALS disease by many different groups. Many current ALS therapeutics are directed toward one or more of these dysfunctional processes. This raises the possibility that patients of a given ALS sub-group might respond better to targeted therapeutics that address the underlying processes at play in their specific subset of the disease. However, the ability to stratify patients into these ALS sub-groups requires identifying clinical biomarkers from tissues or fluids that would be available at diagnosis, for example, blood, cerebrospinal fluid (CSF), or muscle biopsies. In order to identify the best tissues or fluids for biomarkers, one must first collect matched samples from the same patients: First, from tissues where the ALS sub-groups are known to be identifiable (brain tissue), and, second, from tissues or fluids that would be available at diagnosis (muscle, CSF, and/or blood). This project has identified several biobanks and repositories that have those matched samples from dozens of pALS cases. We will leverage these resources to identify biomarkers that can stratify pALS cases into ALS sub-groups.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310198
Entities
People
- Molly Gale Hammell
Organizations
- Cold Spring Harbor Laboratory
- United States Army