Protein can nurture or devastate brain cells, depending on its 'friends,' researchers find

November 12, 2008

Researchers at UT Southwestern Medical Center have uncovered new insights into the "Dr. Jekyll and Mr. Hyde" nature of a protein that stimulates stem-cell maturation in the brain but, paradoxically, can also lead to nerve-cell damage.

In two separate studies in mice scheduled to appear online this week and in an upcoming issue of the Proceedings of the National Academy of Sciences, UT Southwestern research teams studied the protein Cdk5 and discovered both helpful and detrimental mechanisms it elicits in nerve cells.

Dr. Amelia Eisch, assistant professor of psychiatry at UT Southwestern, and her colleagues uncovered a beneficial mechanism of the helpful "Dr. Jekyll" side of the Cdk5 protein, which is also thought to kill brain cells and contribute to neurodegenerative diseases such as Alzheimer's. In the current study, Dr. Eisch found that Cdk5, together with its activating partner molecule p35, helps immature nerve cells become fully functional.

In a separate study, Dr. James Bibb, associate professor of psychiatry at
UT Southwestern, found yet another harmful action of the Cdk5 protein. It can stunt learning and reduce motor control.

Cdk5 is a kinase, which means its job is to interact with all sorts of other proteins inside cells and modify them through a process called protein phosphorylation. Whether Cdk5 nurtures or devastates depends on the state of its partner and the proteins it modifies.

"Like all of us, Cdk5 can influence others, in this case other proteins," Dr. Eisch said. "When Cdk5 messes with hooligans, it causes big trouble. When it hangs with the straight-A students, it actually helps other cells reach their full potential."

Dr. Eisch studied different stages of neurogenesis, or the formation of new nerve cells, in the brains of adult mice and found that the absence of Cdk5 prevents neural stem cells from maturing. She and her group used advanced genetic engineering to create mice in which they could turn off Cdk5 within nerve cells in a specific region of the brain where new neurons are born.

Dr. Eisch found that when Cdk5 is removed from immature nerve stem cells, normal cell division occurs, but the nerve cells never reach maturity. Researchers also removed Cdk5 from neighboring mature nerve cells and discovered that this removal resulted in the production of fewer immature nerve cells.

"The techniques we used have moved us several steps beyond what is usually done in the field," Dr. Eisch said. "We're beginning to assemble a dictionary of what regulates neurogenesis. By understanding what's vital at each stage of development, we hopefully can one day manipulate human nerve cells so that the brain can withstand neurodegenerative diseases such as Alzheimer's."

Dr. Bibb studied the "Mr. Hyde" component of Cdk5. Using a different but equally advanced set of genetic approaches, his team studied the effects of turning Cdk5 to the "dark side" by expressing a shortened form of the Cdk5 activating partner called p25. The group found that when paired with p25 in deep brain structures, Cdk5 had destructive effects on motor coordination and learning in the mice.

Neuropsychiatric illnesses such as schizophrenia, attention deficit hyperactivity disorder and drug addiction involve similar brain pathways as the ones studied and implicated in the "Mr. Hyde" aspect of Cdk5, Dr. Bibb said.

Dr. Bibb also used new technology to reach deeper inside the brain and explore regions beyond those typically examined in conjunction with neurodegenerative diseases. His team used a green fluorescent protein to trace Cdk5's activity in mice, allowing the researchers to examine precisely what was happening in the brain when the Cdk5/p25 pairing was overexpressed.

They found that the overexpression damaged circuitry in the area of the brain that controls movement and reward-based learning. The brain cells lost about half of their connections, or synapses, with other brain cells. This was accompanied by inflammation usually associated with neurodegeneration.

"Once we saw the loss of synapses, we understood why the mice experienced problems with movement and learning," Dr. Bibb said. "Surprisingly, despite the negative effects of putting Cdk5 with p25 in this part of the brain, the cells didn't die. Researchers now have the tools to delve deeper into the brain to study disease. Being unable to control movement, or having psychiatric illness, can be as devastating as memory loss."

Dr. Eisch will next study why immature cells need Cdk5/p35 and why the loss of Cdk5 in neighboring mature nerve cells stopped development.

Dr. Bibb's work will focus on blocking Cdk5 from causing negative reactions and trying to determine how Cdk5/p25 is created.

Other UT Southwestern researchers involved in Dr. Eisch's work were Dr. Diane Lagace, instructor of psychiatry; Dr. David Benavides, resident; and Dr. Bibb. Researchers from the European Institute of Oncology in Italy and Rockefeller University in New York also were involved.

Other UT Southwestern researchers involved in Dr. Bibb's work were Dr. Douglas Meyer, postdoctoral research fellow in psychiatry; Dr. Edmond Richer, former assistant professor of radiology; Dr. Kanehiro Hayashi, postdoctoral researcher in psychiatry; Carly Hale, student research assistant in psychiatry; Dr. Christopher Cowan, assistant professor of psychiatry; and Dr. Peter Antich, professor of radiology. Researchers from the Centers for Disease Control and Prevention, Massachusetts Institute of Technology, Rockefeller University, Yale University School of Medicine and Connecticut Mental Health Center also were involved.

Dr. Janice Kansy, senior research scientist in psychiatry at UT Southwestern, contributed to both papers.

The Canadian Institute of Health Research, the National Institutes of Health and the Cure Alzheimer's Fund supported Dr. Eisch's work.

Dr. Bibb's research was supported in part by the Gulf War Illness Research Program, the National Institute on Drug Abuse and the National Institute of Mental Health.

UT Southwestern

The Massachusetts General Hospital/McLean Hospital Residency Handbook of Psychiatry
by Massachusetts General Hospital and McLean Hospital Residents and Faculties (Author)

Prepared by the residents and faculties of the renowned Massachusetts General Hospital and McLean Hospital, this pocket handbook is packed with succinct, practical, accessible information on the diagnosis and treatment of psychiatric disorders. Major sections include psychiatric emergencies, symptom-based diagnosis and treatment, special populations, and treatment approaches including psychopharmacology. The book is written in a quick-scanning outline format with boxes, tables, and lists to provide high-yield information at a glance.

Studies In Forensic Psychiatry
by Bernard Glueck (Author)

Many of the earliest books, particularly those dating back to the 1900s and before, are now extremely scarce and increasingly expensive. We are republishing these classic works in affordable, high quality, modern editions, using the original text and artwork.

Clinical Psychiatry 2012 (The Clinical Medicine Series)
by Primary Care Software

Topics include: Sleep disorders (insomnia, PMLS, RLS, Narcolepsy...), depression, psychosis, the psychiatric exam, domestic violence, child abuse, substance abuse (tobacco, cocaine, opioid, ETOH, etc), eating disorders, factitious illness, anxiety d/o and many others. Features: complete clinical presentation (common and uncommon manifestations), detailed (not superficial like most texts) information on w/u, labs, Tx, and Ddx. Very extensive treament plans. Full of pearls for primary care physicians, residents and medical students. No other text on the market provides such a collection of succinct and clinically relevant material that can be accessed at the bedside.

Partial Contents: Psych Eval & Testing | Psychosis | Extrapyramidal & Drug SE | Mood D/o | Suicide | Anxiety D/o...

Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry
by Benjamin J. Sadock (Author), Virginia A. Sadock (Author)

The best-selling general psychiatry text since 1972, Kaplan and Sadock's Synopsis of Psychiatry is now in its thoroughly updated Tenth Edition. This complete, concise overview of the entire field of psychiatry is a staple board review text for psychiatry residents and is popular with a broad range of students in medicine, clinical psychology, social work, nursing, and occupational therapy, as well as practitioners in all these areas. The book is DSM-IV-TR compatible and replete with case studies and tables, including ICD-10 diagnostic coding tables. You will also receive access to the complete, fully searchable online text, an online test bank of approximately 100 multiple-choice questions and full answers, and an online image bank.

Blueprints Psychiatry (Blueprints Series)
by Michael J. Murphy (Author), Ronald L. Cowan (Author)

Part of the highly regarded Blueprints series, Blueprints Psychiatry provides students with a concise review of what they need to know in their psychiatry rotations or the Boards. Each chapter is brief and includes pedagogical features such as bolded key words, tables, figures, and key points. A question and answer section at the end of the book includes 100 board-format questions with complete rationales. This edition includes new images, more USMLE study questions, and a Neural Basis section for each major diagnostic category. A companion Website includes a question bank and fully searchable text.

Unhinged: The Trouble with Psychiatry - A Doctor's Revelations about a Profession in Crisis
by Daniel Carlat (Author)

IN THIS STIRRING AND BEAUTIFULLY WRITTEN WAKE-UP CALL, psychiatrist Daniel Carlat exposes deeply disturbing problems plaguing his profession, revealing the ways it has abandoned its essential purpose: to understand the mind, so that psychiatrists can heal mental illness and not just treat symptoms. As he did in his hard-hitting and widely read New York Times Magazine article "Dr. Drug Rep," and as he continues to do in his popular watchdog newsletter, The Carlat Psychiatry Report, he writes with bracing honesty about how psychiatry has so largely forsaken the practice of talk therapy for the seductive—and more lucrative—practice of simply prescribing drugs, with a host of deeply troubling consequences. Psychiatrists have settled for treating symptoms rather than causes, embracing the...

Case Files Psychiatry, Third Edition (LANGE Case Files)
by Eugene Toy (Author), Debra Klamen (Author)

Real life cases for the psychiatry clerkship and shelf-exam 4 STAR DOODY'S REVIEW!
"During medical school, I used similar case review books for various clerkships, including psychiatry. This one stands out because the cases are representative of psychiatry, the explanations are complete yet concise, and the text uses bolded words, tables, and definitions of key terms to help readers understand the essential concepts rather than simply memorizing more data that is likely to be forgotten. The questions are very representative of the type of questions on the shelf-exams and USMLE Step 2, with appropriate descriptions of the correct answers. The first two sections are ideal for students just beginning their clerkship, as they set the groundwork for the basis of...

First Aid for the Psychiatry Clerkship, Third Edition (First Aid Series)
by Latha Stead (Author), Matthew Kaufman (Author), Jason Yanofski (Author)

A high-yield insider's guide to the psychiatry clerkship in the super-effective First Aid format 4 STAR DOODY'S REVIEW (of previous edition)
"This is probably the best overall review book for medical students doing a psychiatry rotation. Its organization and thoroughness are unsurpassed, putting it above similar review books. Students who thoroughly read this book should have no trouble successfully completing their psychiatry clerkship and passing the shelf exam. As course director for the core psychiatry clerkship at my institution, I will recommend this book to students."--Doody's Review Service First Aid for the Psychiatry Clerkship gives you the core information needed to impress on the wards and pass the psychiatry clerkship exam. Written by students who...

Kaplan and Sadock's Concise Textbook of Clinical Psychiatry (Sadock, Kaplan and Sadock Concise Textbook of Clinical Psychiatry)
by Benjamin J. Sadock (Author), Virginia A. Sadock (Author)

This concise textbook is ideal for any student or health care professional who needs an authoritative, readable, affordable text that is sharply focused on clinical psychiatry. It contains the most relevant clinical material from the best-selling Kaplan and Sadock's Synopsis of Psychiatry, Tenth Edition and includes updated information on recently introduced psychiatric drugs. The book is DSM-IV-TR compatible and replete with case studies and tables, including DSM-IV-TR tables. Chapters offer step-by-step guidance on the clinical examination, the psychiatric report, medical assessment of the psychiatric patient, laboratory tests, and signs and symptoms. The major portion of the book covers all psychiatric and substance-related disorders, with special chapters on children, adolescents, and...

Psychiatry 2010 Edition (Current Clinical Strategies)
by Rhoda K Hahn (Author), Lawrence J. Albers (Author), Christopher Reist (Author), MD (Author), MD (Editor), Paul D. Chan (Editor)

This popular handbook is a concise, authoritative guide to psychiatry, including new treatment guidelines. Psychiatry is the most up-to-date reference available for the psychiatry clerkship and residency. Comprehensive and practical, Psychiatry has been used for years by thousands of psychiatrists, residents, and students.