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



Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).


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Publisher Correction: Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.

Nature communications

Aron R, Pellegrini P, Green EW, Maddison DC, Opoku-Nsiah K, Oliveira AO, Wong JS, Daub AC, Giorgini F, Muchowski P, Finkbeiner S

The Autophagy Lysosomal Pathway and Neurodegeneration.

Cold Spring Harbor perspectives in biology

Finkbeiner S