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Division of Natural Sciences & MathematicsDepartment of Biological Sciences

Faculty & Staff

Associate Professor

Daniel Linseman

Dan Linseman

Office: SG Mudd 130

Office Phone: (303) 871-5654

Email: daniel.linseman@du.edu

 

 

 

Degrees

  • 1987 BS, Biology and Chemistry - University of Michigan - Ann Arbor, MI
  • 2000 PhD, Pharmacology - University of Michigan - Ann Arbor, MI
  • 2000-2005 Postdoctoral Fellow/Assistant Research Scientist - Denver Veterans Affairs Medical Center - Denver, CO

Research Interests

Apoptosis is a type of cell death that contributes to several devastating neurodegenerative disorders including Parkinson?s disease (PD) and amyotrophic lateral sclerosis (ALS). Consequently, identification of molecular pathways that regulate neuronal apoptosis is a key to developing novel therapies that slow or halt neurodegenerative diseases. Mitochondria are cell structures responsible for energy generation. In addition, they are the source of most of the oxidative stress cells experience. Importantly, mitochondria also control a specific form of cell death (apoptosis). In many neurodegenerative conditions, activation of a mitochondrial apoptotic cascade is a precursor to neuronal death. Mitochondrial apoptosis is regulated by the Bcl-2 protein family.

Graphic of protein signals

Bcl-2, Bax, and Bim - a molecular triad that regulates cytochrome c release and subsequent caspase activation.  Our laboratory focuses on the regulation, function, and interaction of these Bcl-2 family members during neuronal apoptosis.

Bax is a pro-apoptotic member of this family that induces the activation of pro-death proteases known as caspases. Bax function is inhibited by anti-apoptotic family members such as Bcl-2. The pro-survival action of Bcl-2 is in turn suppressed by pro-apoptotic Bcl-2 homology-3 (BH3)-only proteins (eg., Bim and Puma). The mitochondrial apoptotic cascade plays a key role in neurodegeneration as evidenced by the neuroprotective effects of Bcl-2 overexpression or Bax deletion in animal models of PD or ALS. Moreover, a number of BH3-only proteins have recently been implicated in these neurodegenerative disorders.

Oxidative stress is a principal stimulus for the mitochondrial death pathway. In particular, oxidative damage to mitochondrial lipids and proteins triggers the apoptosis cascade and hinders the cellular production of energy. Bcl-2 displays an antioxidant-like function at mitochondria. Conversely, Bax induces a pro-oxidant state at mitochondria that enhances the apoptosis cascade. A major goal of my laboratory is to discover precisely how these Bcl-2 family proteins regulate mitochondrial oxidative stress.

We have found that small molecule inhibitors of Bcl-2, which mimic the pro-death BH3 domain of Bax, elicit mitochondrial apoptosis in neurons that is blocked by the antioxidant glutathione (GSH). These inhibitors also deplete the endogenous pool of mitochondrial GSH and trigger mitochondrial oxidative stress. Finally, we have made the novel observation that Bcl-2 binds directly to GSH in vitro and this property is antagonized by these same inhibitors. Collectively, these data suggest that Bcl-2 serves as a critical regulator of the mitochondrial GSH pool. In contrast, Bax has the capacity to disrupt the GSH-binding activity of Bcl-2, resulting in depletion of the mitochondrial GSH pool. Loss of this endogenous antioxidant ultimately induces mitochondrial oxidative stress and neuronal apoptosis. Defining the molecular mechanisms by which Bcl-2 and Bax influence the mitochondrial GSH pool may reveal novel proteins that could be targeted to prevent neuronal apoptosis and subsequent neurodegenerative disease.

Link to Linseman's publications through PubMed