David S. Bredt

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David S. Bredt is an American molecular neuroscientist.

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After studies in chemistry at Princeton, Bredt studied medicine at Johns Hopkins School of Medicine where he obtained M.D and Ph.D degrees. He was a student of Solomon H. Snyder, with whom he also co-authored several widely cited papers. [1]

He worked as a postdoctoral fellow in the Department of Neuroscience at Johns Hopkins from 1993 to 1994. [2] He became a 1995 Searle scholar, [3] and received a 1997 Beckman Young Investigators Award. [4]

He worked at the University of California, San Francisco Medical school from 1994 to 2004, first as an assistant professor, [1] later as professor of physiology. [2]

He served as Vice President of Integrative Biology at Eli Lilly and Company from 2004 to 2011. [5] He was elected to the Johns Hopkins University Society of Scholars in 2005. [2] [6]

He worked at Johnson & Johnson from 2011 to 2021 as global head of neuroscience discovery. [7]

Work

Identification of NO synthase and roles for NO in brain and skeletal muscle

While a graduate student in Prof. Solomon Snyder’s lab, Bredt discovered and characterized the family of enzymes that generate nitric oxide (NO). Whereas a single measurement of endogenous NO had previously required complex and laborious methods, Bredt developed a simple, sensitive, and specific assay that monitored the conversion of [3H]arginine to [3H]citrulline. This assay enabled hundreds or thousands of daily measurements of endogenous NO. He first employed this assay to discover that endogenous NO mediates glutamate-linked increases of cyclic GMP in brain (PNAS, 1989). He then biochemically isolated the biosynthetic enzyme, which he named nitric oxide synthase (NOS). In addition, he determined that NOS is a calmodulin-dependent enzyme (PNAS, 1990), which explained how NO is generated rapidly following glutamate-mediated increases in synaptic calcium.

Bredt performed studies that established NO as a diffusible neurotransmitter. He molecularly cloned and sequenced the first NOS cDNA (Nature, 1991), which showed that the N-terminal half of NOS protein is unique and is separated by a calmodulin-binding domain from the C-terminal half, which resembles cytochrome P-450 reductase (Nature, 1991). This protein structure revealed how calmodulin regulates NOS enzyme activity and how redox co-factors enable the complex enzymology of NOS. He immunohistochemically mapped NOS distribution in brain and peripheral tissues (Nature, 1990). He determined that neurons are the primary source of NO throughout the body. In the brain, he found that NOS found in neurons (nNOS) was enriched in specific neuronal populations, and often concentrated at postsynaptic sites, such as cerebellar glomerular synapses, where glutamate receptors activate nNOS. In the peripheral nervous system, he found nNOS enriched in non-adrenergic, non-cholinergic neurons that innervate gastrointestinal and vascular smooth muscle (Nature, 1990).  These findings opened a gateway to investigating how NO participates in diverse physiology processes including aspects of peristalsis and penile erection (Science, 1992).

As a professor at UCSF, Bredt identified the therapeutic potential of modulating NO in brain and skeletal muscle. In brain, Bredt and his team demonstrated that nNOS is enriched at synapses owing to a “PDZ” domain in nNOS that associates with a similar PDZ domain in the synaptic scaffolding protein postsynaptic density 95kD (PSD-95) (Cell, 1996). They showed that PSD-95 physically and functionally links nNOS with NMDA-type glutamate receptors at synapses. As excitotoxic neuronal death associated with cerebral ischemia involves excessive NO production downstream of NMDA receptors (PNAS, 1991), Bredt’s research pointed to exploitation of the antagonism of the NMDA receptor/PSD-95/nNOS complex as a stroke treatment (Journal of Biological Chemistry, 1999), which has shown promising clinical outcomes (Nature Reviews Drug Discovery, 2020).

In addition to finding nNOS in neurons, Bredt helped identify nNOS on skeletal muscle sarcolemma (Nature, 1994), and his team determined that nNOS in muscle associates with dystrophin (Cell, 1995). They discovered a selective loss of nNOS from skeletal muscle sarcolemma in patients with Duchenne and Becker dystrophies, which involve dystrophin mutations (Journal of Experimental Medicine, 1996). Bredt’s team discovered the mechanism by which nNOS is lost from skeletal muscle sarcolemma by identifying that the PDZ domain in nNOS binds to the PDZ in the dystrophin-associated protein syntrophin (Cell, 1996). Through collaboration, they determined the structural correlate to this unexpected PDZ-PDZ interaction (Science, 1999). Today, restoration of NO bioactivity in muscular dystrophies remains a key therapeutic goal.

Protein scaffolding and palmitoylation underlying synaptic signaling and plasticity

Bredt has made contributions to understanding the molecular organization and stability of excitatory synapses. Biochemical studies by Bredt’s team determined that PSD-95 is amongst the most abundant palmitoylated proteins in brain (Neuron, 1998), and that palmitoylation localizes PSD-95 to synaptic sites (Neuron, 1999). They found that synaptic function is regulated dynamically by palmitate cycling on PSD-95 (Cell, 2002). They characterized a family of 24 palmitoyl-transferase enzymes and identified those responsible for regulating PSD-95 (Neuron, 2004). They found that palmitoylated PSD-95 powerfully regulates maturation of excitatory synapses and enhances AMPA receptor clustering (Science, 2000). These discoveries are central to current models of synaptic development, anatomy, and plasticity.[ citation needed ]

TARPs as auxiliary subunits for a neurotransmitter receptor

Bredt, together with Prof. Roger Nicoll, discovered and characterized the first auxiliary subunits for mammalian glutamate neurotransmitter receptor. Bredt and Nicoll determined that a then recently discovered protein, stargazin, links PSD-95 to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subclass of glutamate receptors (Nature, 2000). Stargazin is one member of a family of related proteins, which Bredt termed transmembrane AMPAR regulatory proteins (TARPs), that are differentially distributed in brain (Journal of Cell Biology, 2003). Bredt and Nicoll found that stargazin and related TARPs regulate the synaptic targeting (Nature, 2000), gating (Nature, 2005), and pharmacology (PNAS, 2006) of all AMPA receptors. TARPs not only mediate synaptic function but also bidirectionally regulate synaptic plasticity (Neuron, 2005). This led to the conceptual breakthrough that TARPs are AMPA receptor auxiliary subunits (PNAS, 2005). This model was initially met with resistance, but it is now recognized that ionotropic receptors for many neurotransmitters have auxiliary subunits.

NACHO as a chaperone for a mammalian neurotransmitter receptor

Bredt’s team at Janssen assessed whether analogous protein accessories might enable drug discovery for previously intractable and medically-important nicotinic acetylcholine receptors (nAChRs). Whereas cDNAs encoding nAChRs were discovered in the 1980s, most nAChR subtypes could not be expressed functionally in cell lines. In a study, Bredt’s team used an innovative genome-wide cloning strategy to search systemically for neuronal proteins that could reconstitute the α7 nAChR subtype. They found that assembly of α7 nAChRs requires a novel endoplasmic reticulum protein that Bredt named "nAChR regulator chaperone" (NACHO) (Neuron, 2016), the first client-specific chaperone for a mammalian neurotransmitter receptor family (Cell Reports, 2017). His team found that NACHO engages N‐glycosylation and endoplasmic reticulum chaperone pathways for Alpha-7 nicotinic receptor oligomerization and membrane trafficking (Cell Reports, 2020). By exploiting their genome-wide screening paradigm, they also found an array of other neuronal proteins including Bcl-2 (Nature Communications, 2019), spermidine/spermine N1-acetyltransferase (Nature Communications, 2020) and BARP (Cell Reports, 2019) that conspire with NACHO for functional expression of diverse nACh receptors in brain and peripheral tissues. These discoveries are now enabling biochemical and pharmaceutical studies of limbic α6-containing receptors for psychiatric indications (Cell Reports, 2019), sensory α6-containing receptors for chronic pain (Journal of Clinical Investigation, 2020) and cochlear α9α10 receptors for auditory disorders (PNAS, 2020).

Taken together, Bredt’s discoveries have illuminated unanticipated mediators and mechanisms for neuronal communication. His conceptional advances in neurotransmitter receptor biology have translated into new approaches for treating neuromuscular, neurological, and neuropsychiatric disorders. His papers have been cited more than 75,000 times in the literature.

On November 17, 2021, the Wall Street Journal identified Dr. Bredt as co-author of an anonymous FDA citizen petition to halt phase 3 trials of simufilam, a drug from Cassava Sciences which targets protein misfolding for treatment of Alzheimer's disease. [8] Labaton Sucharow, the law firm filing the petition, acknowledged its clients had taken short positions in the company before the citizen petition, as its clients believed that data had been manipulated in publications and submissions to the FDA [9] The FDA on Feb. 10 closed the petition by stating that “your Petitions are being denied solely on the grounds that your requests are not the appropriate subject of a citizen petition. This response does not represent a decision by the Agency to take or refrain from taking any action relating to the subject matter of your Petitions." On March 30, 2022, PLOS ONE retracted five papers from Cassava’s scientific key advisor including two papers co-authored by Cassava’s vice president of neuroscience. [10] On April 18, 2022, the New York Times published an expose citing nine prominent scientists who questioned the data behind Cassava’s drug. [11] On November 3, 2022, Cassava Sciences filed a lawsuit in federal court against a group that includes Bredt, who Cassava alleges are conducting a "short and distort" campaign, in an effort to “manipulate a stock price and financially benefit from their ‘short positions’ by defaming a company developing a drug for people with Alzheimer’s disease.” [12]

Selected papers

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<span class="mw-page-title-main">Postsynaptic density</span>

The postsynaptic density (PSD) is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. The PSD is in close apposition to the presynaptic active zone and ensures that receptors are in close proximity to presynaptic neurotransmitter release sites. PSDs vary in size and composition among brain regions, and have been studied in great detail at glutamatergic synapses. Hundreds of proteins have been identified in the postsynaptic density, including glutamate receptors, scaffold proteins, and many signaling molecules.

<span class="mw-page-title-main">PDZ domain</span>

The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components. Proteins with these domains help hold together and organize signaling complexes at cellular membranes. These domains play a key role in the formation and function of signal transduction complexes. PDZ domains also play a highly significant role in the anchoring of cell surface receptors to the actin cytoskeleton via mediators like NHERF and ezrin.

<span class="mw-page-title-main">DLG4</span> Mammalian protein found in Homo sapiens

PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene.

<span class="mw-page-title-main">DLG1</span> Protein-coding gene in the species Homo sapiens

Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene.

<span class="mw-page-title-main">NOS1</span> Protein-coding gene in the species Homo sapiens

Nitric oxide synthase 1 (neuronal), also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene.

<span class="mw-page-title-main">PICK1</span> Protein-coding gene in the species Homo sapiens

Protein Interacting with C Kinase - 1 is a protein that in humans is encoded by the PICK1 gene.

<span class="mw-page-title-main">DLG2</span> Protein-coding gene in the species Homo sapiens

Disks large homolog 2 (DLG2) also known as channel-associated protein of synapse-110 (chapsyn-110) or postsynaptic density protein 93 (PSD-93) is a protein that in humans is encoded by the DLG2 gene.

<span class="mw-page-title-main">GRIN2B</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B, is a protein that in humans is encoded by the GRIN2B gene.

<span class="mw-page-title-main">Syntrophin, alpha 1</span> Protein-coding gene in the species Homo sapiens

Alpha-1-syntrophin is a protein that in humans is encoded by the SNTA1 gene. Alpha-1 syntrophin is a signal transducing adaptor protein and serves as a scaffold for various signaling molecules. Alpha-1 syntrophin contains a PDZ domain, two Pleckstrin homology domain and a 'syntrophin unique' domain.

In neuroscience, synaptic scaling is a form of homeostatic plasticity, in which the brain responds to chronically elevated activity in a neural circuit with negative feedback, allowing individual neurons to reduce their overall action potential firing rate. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections by decreasing the strength of each synapse by the same factor, so that the relative synaptic weighting of each synapse is preserved.

Glutamate receptor-interacting protein (GRIP) refers to either a family of proteins that bind to the glutamate receptor or specifically to the GRIP1 protein within this family. Proteins in the glutamate receptor-interacting protein (GRIP) family have been shown to interact with GluR2, a common subunit in the AMPA receptor. This subunit also interacts with other proteins such as protein interacting with C-kinase1 (PICK1) and N-ethylmaleimide-sensitive fusion protein (NSF). Studies have begun to elucidate its function; however, much is still to be learned about these proteins.

<span class="mw-page-title-main">Glutamate (neurotransmitter)</span> Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

References

  1. 1 2 Karen Kreeger (2 May 1992) Hot Scientists Have Philosophies In Common The Scientist
  2. 1 2 3 Society of Scholars Inducts New Members The JHU Gazette. 23 May 2005. Retrieved 16 December 2013
  3. ↑ Scholar Profile David S. Bredt
  4. ↑ "David S. Bredt". Arnold and Mabel Beckman Foundation. Retrieved 1 August 2018.
  5. ↑ Jonathan D. Rockoff (24 February 2011) Lilly's Neuroscience Research Chief Resigns The Wall Street Journal. Retrieved 16 December 2013
  6. ↑ Julie Blanker (September 2005) Alumni NotesAlumni Notes Johns Hopkins Magazine. Retrieved 16 December 2013
  7. ↑ Jonathan D. Rockoff (3 March 2011 J&J Poaches Lilly's Neurological Research Chief The Wall Street Journal . Retrieved 16 December 2013
  8. ↑ Dave Michaels (November 2021) "Wall Street Journal". Retrieved 7 December 2021
  9. ↑ Third Supplement from Labaton Sucharow to Citizens Petition Associated with Cassava Sciences Inc (November 2021) "FDA Dockets". Retrieved 7 December 2021
  10. ↑ The PLOS ONE Editors (30 March 2022). "Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine". PLOS ONE. 17 (3): e0266629. Bibcode:2022PLoSO..1766629.. doi: 10.1371/journal.pone.0266629 . ISSN   1932-6203. PMC   8967007 . PMID   35353864.
  11. ↑ Mandavilli, Apoorva (2022-04-18). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. ISSN   0362-4331 . Retrieved 2022-04-23.
  12. ↑ Patel, Anviksha. "Short sellers hit back at Cassava lawsuit against them: 'We stand behind everything we wrote'". Market Watch. Retrieved 10 January 2023.
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