Randal Tibbetts

Research Description:

Investigating the Molecular Pathogenesis of ALS and FTD

Our laboratory investigates the molecular mechanisms underlying Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), two devastating neurodegenerative disorders that share overlapping clinical and genetic features yet currently lack effective therapies.

We focus on the 10–15% of cases caused by inherited mutations to uncover fundamental mechanisms that drive disease initiation and progression. By understanding how defined genetic alterations disrupt cellular pathways, we aim to identify actionable targets for therapeutic intervention.

To achieve this, we employ an integrated “fly-to-human” discovery pipeline:

1. 1. 1. 1. Discovery
            We leverage the genetic power of Drosophila to identify pathways that modify the toxicity of ALS/FTD-associated mutations.
         2. Mechanistic Validation
            Candidate pathways are translated into human systems using induced pluripotent stem cell (iPSC)-derived motor neurons and brain organoids to define disease-relevant mechanisms.
         3. Therapeutic Testing
            Promising modifiers are evaluated in gene-edited mouse models to assess their potential for therapeutic benefit.

Using this cross-species strategy, we have identified axon guidance and endolysosomal pathways as key regulators of neurodegeneration caused by ALS/FTD-associated mutations in the ubiquitin chaperone, UBQLN2.  Our ongoing work seeks to define precisely how ALS/FTD-linked mutations in UBQLN2 and other ALS/FTD-associated genes disrupt these pathways and to translate these insights into strategies capable of preventing or reversing neuronal dysfunction.

In addition, ATM-independent pathways mediate CREB autoinhibition in response to a variety of growth-inhibitory stimuli, whereas signaling through the pro-growth mTOR pathway promotes CREB dephosphorylation (Fig. 1). In addition to defining these pathways and elucidating biochemical mechanisms of autoinhibition, we are currently investigating functional impacts of cancer associated mutations that may diminish CREB autoinhibition. The importance of these pathways in tumor suppression and other CREB-mediated processes is being tested using CREB gene-edited mice. b. Novel roles of RNA-binding proteins in DNA damage repair and tumor suppression. A second project is focusing on emergent roles for RNA-bindings proteins (RBPs) in DNA damage-dependent alternative splicing, DNA repair, and tumor suppression. We are elucidating pathways controlling DNA damage-dependent changes in alternative splicing and modeling the implications of these changes in mice using CRISPR/CAS9-mediated genome editing in mice.

The long-term goal of these studies is to understand fundamental aspects of DNA damage repair and response that can be used to guide radio- and chemotherapeutic strategies for cancer patients. (ii) Molecular pathogenesis of ALS. ALS is a fatal neurodegenerative disease that affects motor neurons. Recent genetic advances have identified genes that are critically involved in the ALS disease process, including the RNA-binding proteins TDP-43 and FUS/TLS, the uncharacterized open reading frame, C9ORF72, and UBQLN2. We are using cell culture, Drosophila melanogaster (fruit fly), and mouse models to understand how ALS-associated mutations in these genes instigate neurodegeneration. We are particularly interested in how ALS mutations in the ubiquitin chaperone UBQLN2 promote its misfolding and aggregation, leading to disruption of protein clearance mechanisms and neuron death. The long-term goal of this work is to identify key pathways that may be amenable to therapeutic intervention in ALS and related dementias.

Representative Publications:
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