About

Dr. Stu Feinstein is a Professor of Molecular, Cellular and Developmental Biology at UC Santa Barbara and serves as Co-Director of the Neuroscience Research Institute. He earned his undergraduate degree in Biochemistry from the University of California, Berkeley, and his Ph.D. from the Department of Biochemistry and Biophysics at the University of California School of Medicine, San Francisco. Following his doctoral studies, he was a postdoctoral fellow in the Department of Neurobiology at Stanford University School of Medicine until 1986, when he joined UCSB faculty. Dr. Feinstein has served as a grant reviewer for the National Institutes of Health, the National Science Foundation, and the Cancer Research Coordinating Committee of California. He has been recognized with several awards, including the UCSB Distinguished Teaching Award, the 2011 National Academies Education Fellow in the Life Sciences, and the 2017 Chancellor’s Award for Excellence in Undergraduate Research. His research focuses on the normal and pathological actions of the microtubule-associated protein tau, which plays a critical role in regulating microtubule dynamics and neuronal cell biology. His investigations employ protein biochemistry, molecular cell biology, and biophysics, often in collaboration with colleagues at UCSB. His work aims to understand the mechanistic details of tau's regulation of microtubules and its involvement in neurodegenerative diseases such as Alzheimer's, examining processes like tau oligomerization, fragmentation, aggregation, and tau's role at microtubule ends.

Research topics

• Biology
• Biophysics
• Cell biology
• Chemistry
• Crystallography
• Computer Science
• Biochemistry
• Cancer research
• Stereochemistry
• Medicine
• Geometry
• Materials science
• Ecology
• Polymer chemistry
• Physics

Selected publications

• Regulation of microtubule radial structure by competition between Tau and paclitaxel: Binding and x-ray scattering studies

  Biophysical Journal · 2025-12-01

  article
  PublisherDOI

• A model of the microtubule cytoskeleton of the axon initial segment in mixtures of tubulin, tau, and GTP

  Biophysical Journal · 2025-12-01

  review
  PublisherDOI

• Serendipity in Scientific Research

  Journal of Trial and Error · 2024-04-08 · 2 citations

  articleOpen accessSenior author

  Serendipity refers to the combination of “accident” and “sagacity”; an unexpected and unpredicted event which is noticed by an agent with the right skills to make the most of it. Famous examples include Jocelyn Bell’s discovery of pulsars which was made after she noticed an unusual output from a radio telescope (Arfini, 2023). Bell noticed and unpredicted output on the graphical trace and followed it up, eventually discovering the existence of pulsars. The rate of serendipitous discovery in science is unclear, although it has been estimated to be high (Thagard, 2012). This series is meant not only to add to the repertoire of serendipity stories, but to begin treating these tales as members in a growing archive, in which we attend to the role of chance and the unexpected in our rational pursuits of knowledge. Scientists here will share how accidents and reason intertwined in their practice, and researchers of serendipity will unpack how that happens.

  PublisherOA PDFDOI

• Nerve Growth Factor: its Role in Neuronal Growth and Maintenance

  2024-10-10

  book-chapterSenior author

  The discovery of nerve growth factor (NGF) moved developmental neurobiology into the molecular era and allowed a number of phenomenological observations to be explained in molecular terms. It was known prior to the discovery of NGF that the process of neuronal cell death determines the final size of a given neuronal population and that cell death occurs at the time that the nerve fibers reach their targets (16). Furthermore, the size of the target influences the extent of cell death suggesting that the targets secrete trophic factors which neurons require for survival. NGF is the first of these trophic factors to be identified and purified. The initial experiments which led to this discovery involved transplantation of mouse sarcomas to the body wall of chick embryos and the observation that the sympathetic ganglia became hypertrophied and vigorously sprouted neurites (27). Since grafting of the sarcoma onto the chorioallantoic membrane gave the same results it was inferred that the sarcoma secreted a diffusible factor (28). In tissue culture it was observed that extracts of the sarcoma enhanced the survival of sensory and sympathetic ganglia and stimulated neurite outgrowth (29). This in turn provided the basis of a biological assay for the purification of the active factor (NGF), and the preparation of NGF antibody (6). The critical in vivo dependency of sympathetic neurons on NGF was then demonstrated by the failure of virtually all sympathetic neurons to develop when NGF antibody was injected into newborn mice, rats or other mammals (26). More recent experiments also showed that exposure of fetal rats to NGF antibody via placental transfer significantly reduced the number of sensory neurons which developed normally (20).

  PublisherDOI

• Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid-Liquid Phase Separated Coacervates

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-17

  preprintOpen access

  Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein, which binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer's and other neurodegenerative diseases. Here, we studied the interactions between full length human protein tau and other negatively charged binding substrates, as revealed by differential-interference-contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, -1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, -1e) mixed with zwitterionic 1,2dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid-liquid phase separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes exhibited distinct types of morphologies. This included, large ≈20-30 micron tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles, and tau-mediated finite-size assemblies of small liposomes. As the ionic strength of the solution was increased to near and above physiological salt concentrations for 1:1 electrolytes (≈150 mM), AL-tau complexes remained stable while tau self-coacervate droplets were found to dissolve indicative of breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen facing monolayer of the axon plasma membrane suggesting the possibility of transient yet robust interactions at physiologically relevant ionic strengths.

  PublisherOA PDFDOI

• Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles

  Nature Communications · 2024 · 12 citations

  • Biophysics
  • Crystallography
  • Chemistry

  ), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αβ-tubulin oligomers in the IN are crosslinked by tau's MT binding repeats, which also link αβ-tubulin oligomers to αβ-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.

  PublisherOA PDFDOI

• Mixtures of Intrinsically Disordered Neuronal Protein Tau and Anionic Liposomes Reveal Distinct Anionic Liposome-Tau Complexes Coexisting with Tau Liquid–Liquid Phase-Separated Coacervates

  Langmuir · 2024-09-28 · 2 citations

  article

  Tau, an intrinsically disordered neuronal protein and polyampholyte with an overall positive charge, is a microtubule (MT) associated protein that binds to anionic domains of MTs and suppresses their dynamic instability. Aberrant tau-MT interactions are implicated in Alzheimer’s and other neurodegenerative diseases. Here, we studied the interactions between full-length human protein tau and other negatively charged binding substrates, as revealed by differential interference contrast (DIC) and fluorescence microscopy. As a binding substrate, we chose anionic liposomes (ALs) containing either 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS, −1e) or 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG, −1e) mixed with zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to mimic anionic plasma membranes of axons where tau resides. At low salt concentrations (0 to 10 mM KCl or NaCl) with minimal charge screening, reaction mixtures of tau and ALs resulted in the formation of distinct states of AL-tau complexes coexisting with liquid–liquid phase-separated tau self-coacervates arising from the polyampholytic nature of tau containing cationic and anionic domains. AL-tau complexes (i.e. tau-lipoplexes) exhibited distinct types of morphologies. This included large ∼20–30 μm tau-decorated giant vesicles with additional smaller liposomes with bound tau attached to the giant vesicles and tau-mediated finite-size assemblies of small liposomes. As the salt concentration was increased to near and above 150 mM for 1:1 electrolytes, AL-tau complexes remained stable, while tau self-coacervate droplets were found to dissolve, indicative of the breaking of (anionic/cationic) electrostatic bonds between tau chains due to increased charge screening. The findings are consistent with the hypothesis that distinct cationic domains of tau may interact with anionic lipid domains of the lumen-facing monolayer of the axon’s plasma membrane, suggesting the possibility of transient yet robust interactions near relevant ionic strengths found in neurons.

  PublisherDOI

• Data from Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics

  2023-03-31

  preprintOpen access

  <div>Abstract<p>Bis(4-fluorobenzyl)trisulfide (BFBTS) is a synthetic molecule derived from a bioactive natural product, dibenzyltrisulfide, found in a subtropical shrub, Petiveria allieacea. BFBTS has potent anticancer activities to a broad spectrum of tumor cell lines with IC<sub>50</sub> values from high nanomolar to low micromolar and showed equal anticancer potency between tumor cell lines overexpressing multidrug-resistant gene, <i>MDR1</i> (MCF7/adr line and KBv200 line), and their parental MCF7 line and KB lines. BFBTS inhibited microtubule polymerization dynamics in MCF7 cells, at a low nanomolar concentration of 54 nmol/L, while disrupting microtubule filaments in cells at low micromolar concentration of 1 μmol/L. Tumor cells treated with BFBTS were arrested at G<sub>2</sub>-M phase, conceivably resulting from BFBTS-mediated antimicrotubule activities. Mass spectrometry studies revealed that BFBTS bound and modified β-tubulin at residue Cys12, forming β-tubulin-SS-fluorobenzyl. The binding site differs from known antimicrotubule agents, suggesting that BFBTS functions as a novel antimicrotubule agent. BFBTS at a dose of 25 mg/kg inhibited tumor growth with relative tumor growth rates of 19.91%, 18.5%, and 23.42% in A549 lung cancer, Bcap-37 breast cancer, and SKOV3 ovarian cancer xenografts, respectively. Notably, BFBTS was more potent against MDR1-overexpressing MCF7/adr breast cancer xenografts with a relative tumor growth rate of 12.3% than paclitaxel with a rate of 43.0%. BFBTS displays a novel antimicrotubule agent with potentials for cancer therapeutics. [Mol Cancer Ther 2009;8(12):3318–30]</p></div>

  PublisherDOI

• Data from Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery

  2023-03-31

  preprintOpen access

  <div>Abstract<p>Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.</p><p><b>Significance:</b> This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. <i>Cancer Res; 78(3); 817–29. ©2017 AACR</i>.</p></div>

  PublisherDOI

• Synchrotron X-ray study of intrinsically disordered and polyampholytic Tau 4RS and 4RL under controlled ionic strength

  The European Physical Journal E · 2023-08-31 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R01NS024387

  NIH · $251k · 1990

• NIH Grant R01EY010739

  NIH · $483k · 1999

• NIH Grant R01NS035010

  NIH · $3.4M · 2013

Frequent coauthors

• Leslie Wilson

  65 shared

• Cyrus R. Safinya

  University of California, Santa Barbara

  46 shared

• Myung Chul Choi

  Korea Institute of Brain Science

  37 shared

• Peter J. Chung

  University of California, Santa Barbara

  31 shared

• Nichole E. LaPointe

  University of California, Santa Barbara

  30 shared

• Youli Li

  29 shared

• Herbert P. Miller

  University of California, Santa Barbara

  26 shared

• Monte J. Radeke

  25 shared

Labs

• feinstein scPI

Education

• B.S., Biochemistry

  University of California, Berkeley

• Ph.D., Biochemistry and Biophysics

  University of California School of Medicine, San Francisco

Awards & honors

• UCSB Distinguished Teaching Award
• Chancellor’s Award for Excellence in Undergraduate Research…
• National Academies Education Fellow in the Life Sciences (20…