Steve Finkbeiner, MD, PhD

Director, Taube/Koret Center for Neurodegenerative Disease Research
Senior Investigator and Associate Director, Gladstone Institute of Neurological Disease
Department of Neurology
+1 415 734-2508
Research Description: 

Areas of Investigation: Research in our laboratory focuses on molecular mechanisms of plasticity and neurodegeneration. A long-term goal of our research is to understand how neuronal activity elicits changes in gene expression that are important for learning and memory. We also aim to understand how an inherited genetic mutation leads to neuronal dysfunction and degeneration in Huntington’s disease (HD).

Significance: To convert brief experiences into long-term memories, new gene expression is needed. Understanding how brief neuronal activity regulates gene expression could help us understand how memories are formed. We may also develop new strategies to help people with cognitive disturbances such as those seen in HD. HD is the most common inherited neurodegenerative disorder and belongs to a family of 12 neurological diseases, which are caused by the same type of mutation an abnormal expansion of a homomeric polyglutamine stretch within the affected protein.

We use cellular, molecular, biochemical, imaging, and electrophysiological approaches to elucidate the molecular mechanisms of plasticity and neurodegeneration. We have developed primary culture models of activity-dependent gene transcription and of HD. These models faithfully recapitulate critical features of these processes and allow us to test hypotheses about their underlying mechanisms. Selected findings are evaluated further in genetically modified mice.

Contributions: We have contributed to the understanding of mechanisms of plasticity and neurodegeneration in several ways. We found that proteins bound to the cytoplasmic portion of one subtype of glutamate receptor, the N-methyl-D-aspartate receptor, play a critical role coupling local Ca2+ influx through the channel to elicit adaptive gene transcription in neurons. This may be a general mechanism by which diverse Ca2+ channels achieve specific and distinct neuronal responses. We developed a neuronal model that faithfully recapitulates key features of HD. We showed that the nucleus is a critical subcellular site in which mutant huntingtin (the affected protein in HD) induces neurodegeneration. However, mutant huntingtin need not aggregate into inclusions to induce neurodegeneration. Recently, we developed a new automated imaging system that we call a robotic microscope. The instrument enables us to track living neurons over long time periods and to, quantify quickly the adaptive or maladaptive responses of thousands of neurons. Along with special statistical methods, we now have the ability to determine whether and to what extent a variable that is observed on one day can predict the fate of that neuron on another day. This ability will enable us to unravel confounding cause-and-effect mechanisms.

Questions Addressed in Ongoing Studies

- How does the C-terminus of the NMDA receptor couple Ca2+ influx to gene expression?
- What are the gene targets of the NMDA receptor and to what extent do they differ from gene targets of other neuronal - Ca2+ channels?
- What role does subsynaptic protein translation play in synapse-specific gene expression, learning, and memory?
- How does the polyglutamine expansion induce selective degeneration in certain types of neurons?
- What roles do ubiquitination and proteasome function play in neurodegeneration?
- What is the normal function of huntingtin?
- Which is a better predictor of neurodegeneration inclusion body formation or more soluble but malfolded versions of huntingtin?

Primary Thematic Area: 
Secondary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Research Summary: 
Molecular Mechanisms of Synaptic Plasticity and Neurodegeneration



A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway.

bioRxiv : the preprint server for biology

Proteostasis Consortium, Overall coordination, Elsasser S, Elia LP, Morimoto RI, Powers ET, Harvard Medical School group, Elsasser S, Finley D, University of California, San Francisco and Gladstone Institutes group I, Costa B, Budron M, Tokuno Z, Wang S, Iyer RG, Barth B, Mockler E, Elia LP, Finkbeiner S, University of California, San Francisco group II, Gestwicki JE, Northwestern University group, Richardson RAK, Stoeger T, Morimoto RI, Scripps Research Institute group, Tan EP, Xiao Q, Cole CM, Massey LEA, Garza D, Powers ET, Kelly JW, Stanford University group, Rainbolt TK, Chou CC, Masto VB, Frydman J, New York University group, Nixon RA

AutoComet: A fully automated algorithm to quickly and accurately analyze comet assays.

Redox biology

Barb? L, Lam S, Holub A, Faghihmonzavi Z, Deng M, Iyer R, Finkbeiner S

Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects.


Workman MJ, Lim RG, Wu J, Frank A, Ornelas L, Panther L, Galvez E, Perez D, Meepe I, Lei S, Valencia V, Gomez E, Liu C, Moran R, Pinedo L, Tsitkov S, Ho R, Kaye JA, Answer ALS Consortium, Thompson T, Rothstein JD, Finkbeiner S, Fraenkel E, Sareen D, Thompson LM, Svendsen CN

The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism.

Cell genomics

Bressan E, Reed X, Bansal V, Hutchins E, Cobb MM, Webb MG, Alsop E, Grenn FP, Illarionova A, Savytska N, Violich I, Broeer S, Fernandes N, Sivakumar R, Beilina A, Billingsley KJ, Berghausen J, Pantazis CB, Pitz V, Patel D, Daida K, Meechoovet B, Reiman R, Courtright-Lim A, Logemann A, Antone J, Barch M, Kitchen R, Li Y, Dalgard CL, American Genome Center, Rizzu P, Hernandez DG, Hjelm BE, Nalls M, Gibbs JR, Finkbeiner S, Cookson MR, Van Keuren-Jensen K, Craig DW, Singleton AB, Heutink P, Blauwendraat C

Frontotemporal Dementia Patient Neurons With Progranulin Deficiency Display Protein Dyshomeostasis.

bioRxiv : the preprint server for biology

Elia L, Herting B, Alijagic A, Buselli C, Wong L, Morrison G, Prado MA, Paulo JA, Gygi SP, Finley D, Finkbeiner S