Jian Feng , Ph.D.
Associate Professor
Department of Physiology and
Biophysics
School of Medicine &
Biomedical Sciences
State University of New York at
Buffalo
124 Sherman Hall
Buffalo, NY 14214
Director
Neurodegenerative Disease Group
New York State Center of Excellence in Bioinformatics and Life Sciences
701 Ellicott Street
Buffalo, NY 14203
Email: jianfeng@buffalo.edu
Office Address: BRB 549 (South Campus), B4-319 (COE)
Tel: (716) 829-2345 (South Campus), (716) 881-8968 (COE)
Fax: (716) 829-2699
Research
Interests:
My research is focused on the molecular and cellular mechanisms of Parkinson’s disease, a common neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in substantia nigra. Long-term epidemiological studies, particularly those performed on twins, strongly suggest that environmental toxins play a critical role in the common, late-onset forms of PD, whereas mutations of several genes clearly cause rare forms of familial, early-onset Parkinson’s disease. Among these genes, parkin is frequently mutated in familial as well as idiopathic Parkinson’s disease, especially in cases with an early age at onset.
We are studying the molecular and cellular mechanisms of Parkinson’s disease by examining how parkin and environmental toxins might impinge on the same molecular targets to influence the survival of nigral dopaminergic neurons. Microtubules emerge as a common target on which parkin and some PD environmental toxins act in opposing manners11. It appears that many functions of parkin are linked to its strong interactions with microtubules, which play an essential role in the survival of nigral dopaminergic neurons. Our studies have identified at least four aspects of parkin that are linked to microtubules:
(I) Parkin directly binds to1 and stabilizes microtubules against depolymerizing toxins through strong and redundant interactions mediated by three independent domains of parkin6. This action protects nigral dopaminergic neurons against microtubule-depolymerizing toxins such as rotenone14. Midbrain dopaminergic neurons are particularly vulnerable to microtubule depolymerization because accumulation of DA vesicles after microtubule disruption leads to increased cytosolic dopamine concentration, elevated oxidative stress and ensuing cell death7. In fact, all monoaminergic neurons, including serotonergic neurons12, are killed by rotenone and other microtubule-depolymerizing drugs through the same mechanism, while non-monoaminergic neurons are much less sensitive to these toxins because their neurotransmitters (Glu, GABA, Ach, etc.) cannot be easily oxidized and cause oxidative stress. Parkin, but not its PD linked mutants, suppresses the selective toxicity of microtubule-depolymerizing PD toxins such as rotenone by stabilizing microtubules and attenuating MAP kinase activation14. Consistent with this, microtubule stabilization by chemicals such as taxol7 or by activation of intracellular signaling pathway8,10, significantly attenuates rotenone toxicity.
(II) Many substrates of parkin, e.g. dopamine transporter5, are transmembrane proteins or membrane-associated proteins, which are synthesized in the endoplasmic reticulum (ER). As the ER is attached to microtubules, the association of parkin with microtubules provides an ideal location for the efficient ubiquitination of misfolded substrates that are retrotranslocated from the ER. By ubiquitinating and degrading misfolded dopamine transporter (DAT), parkin increases the proper assembly of DAT oligomers in the ER and thus facilitates the cell surface expression of DAT and enhances the precision of dopaminergic transmission5. Parkin mutants not only lose this critical function but also make DA neurons more prone to toxicity caused by misfolded substrates such as DAT, which is only expressed in DA neurons.
(III) Parkin plays a significant role in the formation of protein aggregates termed Lewy bodies, which are not found in PD patients with parkin mutations. When proteasomes are overwhelmed by misfolded proteins, parkin and its substrates are recruited to the centrosome along microtubules2. The direct binding with HDAC6 mediates the reversible recruitment of parkin to or from the centrosome, depending on the levels of proteasome inhibition13. The parkin-HDAC6 complex forms a positive feedback mechanism to engage misfolded parkin substrates for their continued ubiquitination by parkin as they are being transported along microtubules through interaction with HDAC6.
(IV) Parkin regulates the expression of many nuclear-encoded mitochondrial proteins, such as monoamine oxidases A and B9. It appears that parkin, through tight binding with microtubules, may downregulate the nuclear availability of transcription factors critically involved in the expression of these mitochondrial proteins. The ability of parkin to suppress the expression of MAO protects DA neurons against oxidative stress caused by dopamine4.
Our current research continues along this microtubule-centric theme. In addition to in vitro experiments, we are utilizing animal models and human induced pluripotent stem cells to study the functions of parkin and the impact of its mutations both in vivo in mice and in human midbrain DA neurons. Our long-term goal is to understand why these human neurons degenerate when parkin is mutated. The knowledge may contribute to improved therapy of Parkinson’s disease.
Primary
Publications:
(14) Y. Ren, H. Jiang, F. Yang, K. Nakaso, and J. Feng (2009).
Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating MAP kinase activation.
J. Biol. Chem. 284:4009-4017. [PDF file]
(13) Q. Jiang, Y. Ren, and J. Feng (2008).
Direct Binding with Histone Deacetylase 6 Mediates the Reversible Recruitment of Parkin to the Centrosome.
J. Neurosci. 28:12993–13002. [PDF file]
(12) Y. Ren and J. Feng (2007).
Rotenone Selectively Kills Serotonergic Neurons through a Microtubule-dependent Mechanism.
J. Neurochem. 103:303-311. [PDF file]
(11) J. Feng (2006).
Microtubule: a Common Target for Parkin and Parkinson’s Disease Toxins.
Neuroscientist. 12:469-476. [PD
(10) Q. Jiang, Z. Yan, and J. Feng (2006).
Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons.
J. Biol. Chem. 281:29391-29400.
[PDF file]
(9) H. Jiang, Q. Jiang, W. Liu and J. Feng (2006).
Parkin Suppresses the Expression of Monoamine Oxidases.
J. Biol. Chem. 281:8591-8599. [PDF file]
(8) Q. Jiang, Z. Yan, and J. Feng (2006).
Activation of Group III Metabotropic Glutamate Receptors Attenuates Rotenone Toxicity on Dopaminergic Neurons through a Microtubule-dependent Mechanism.
J. Neurosci.
26:4318-4328. [PDF file]
(7) Y. Ren, W. Liu, H. Jiang, Q. Jiang, and J. Feng (2005).
Selective Vulnerability of Dopaminergic Neurons to Microtubule Depolymerization.
J. Biol. Chem. 280:34105-34112. [PDF file] [Media Coverage]
(6) F. Yang, Q. Jiang, J. Zhao, Y. Ren, M.D. Sutton and J. Feng (2005).
Parkin Stabilizes Microtubules through Strong Binding Mediated by Three Independent Domains.
J. Biol. Chem. 280:17154-17162. [PDF file]
(5) H. Jiang, Q. Jiang and J. Feng (2004).
Parkin Increases Dopamine Uptake by Enhancing the Cell Surface Expression of Dopamine Transporter.
J. Biol. Chem. 279:54380-54386. [PDF
file]
(4) H. Jiang, Y. Ren, J. Zhao and J. Feng (2004).
Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis.
Hum. Mol. Genet. 13: 1745-1754. [PDF file]
(3) J. Feng (2003).
Genetic factors in Parkinson’s disease and potential therapeutic targets.
Curr. Neuropharmacol. 1:
301-313. [PDF file]
(2) J. Zhao, Y. Ren, Q. Jiang and J. Feng (2003).
Parkin is recruited to the centrosome in response to inhibition of proteasomes.
J. Cell Sci. 116:
4011-4019. [PDF file]
(1) Y. Ren, J. Zhao and J. Feng (2003).
Parkin binds to a/β tubulin and increases their ubiquitination and degradation.
J. Neurosci. 23:
3316-3324. [PDF file]
Biographical Information:
Education:
1993-1997:
Ph.D. Biochemistry (1997),
1986-1990:
B.Sc. Biochemistry (1990)
Academic Appointments:
2006-Present: Director
Neurodegenerative Disease Group
New York State Center of Excellence in Bioinformatics and Life Sciences
State University of New York at Buffalo, Buffalo, NY.
2005-Present: Associate Professor (Tenured)
Department of Physiology and Biophysics
School of Medicine and Biomedical Sciences
State University of New York at Buffalo, Buffalo, NY.
2000-2005: Assistant Professor
Department of Physiology and Biophysics
School of Medicine and Biomedical Sciences
State University of New York at Buffalo, Buffalo, NY.
1997-2000: Postdoctoral Associate
Laboratory of Molecular and Cellular Neuroscience
The Rockefeller University, New York, NY.
Research advisor: Paul
Greengard, Ph.D.
Awards:
·
Rapid
Response Innovation Award, Michael J. Fox Foundation (03/08).
·
Top 100 Principle
Investigators,
· Visionary Inventor Award, State University of New York at Buffalo (5/05).
· Promising Inventor Award, State University of New York (11/04).
· Top 100 Federal Grantee, State University of New York at Buffalo (11/02)
· Young Investigator Achievement Award, SUNY-Buffalo (5/02).
· Theodore and Vada Stanley Foundation Research Award (8/98-7/00).
· Ralph R. Braund Young Investigator Award in Cancer Research, Univ. of Tennessee and Memphis Cancer Society (4/97).
· Alma and Hal Reagan Fellowship in Cancer Research, Univ. of Tennessee (7/95 - 6/97).
· Travel Award from the American Society of Hematology (10/96).
Membership:
American Society of Cell Biology
American Society for Pharmacology and
Experimental Therapeutics
Leisure Writing:
Last updated July 8, 2009.