Section: Research

Postdoctoral Position Available

Athena Andreadis, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cell Biology

Other Affiliation(s):
   Program in Neuroscience

Genetic Causes of Abnormal Brain Development

Our genes define us as a species, but our neuronal synapses define us as individuals. Normal brain development is a complex process that requires the coordinated expression of many genes. Understanding this regulation is prerequisite to elucidating the genetic causes of abnormal brain development. I examine alternative splicing, a gene regulatory mechanism vital for the proper functioning of the entire organism, and the nervous system in particular. Alternative splicing, which occurs in 70% of vertebrate genes, results in the production of multiple variants from a single gene and is a major contributor to proteomic complexity.

My chosen model is the human tau gene, whose product is instrumental in the function of the axon (the information transmitter for each neuron). Via the process of alternative splicing, tau gives rise to multiple products that control axonal morphology and stability. Disturbances in tau splicing result in disruption of the axon and formation of pathological tau structures called neurofibrillary tangles. Dementia sufferers display these tangles which correlate with the severity of common developmental and degenerative neurological disorders (Alzheimer's disease, progressive supranuclear palsy, Pick's disease, corticobasal degeneration). The second most common dementia after Alzheimer's, frontotemporal dementia with Parkinsonism, is directly caused by misregulations in tau alternative splicing. The disease is caused by wild-type proteins present in incorrect ratios -- a paradigm of a dosage error effect. Finally, tau also plays an important role in development: individuals with microdeletions or microduplications of the tau locus suffer from developmental delay and learning disabilities, and tau null mice display learning disabilities and muscle defects.

My dissection of the tau system with molecular and cellular tools isbeginning to clarify the role of tau variants in neuronal morphology and fate,the identity and role of molecules that interact with tau protein and the mechanism of action of regulators which modulate the splicing of its gene. All these molecules almost certainly control nervous system function, and may eitherprevent or promote tangle formation. This research will give insights into 1)neuronal-specific splicing regulation, 2) the regulatory cascades within the normal brain and 3) the causes of dementia, with the long term view of preventing or curing neuronal loss. This type of research forms part of the bottom-up approach in answering one of the major questions both within and beyond science -- how the brain creates a mind (the Binding Problem).

Ongoing Projects

• Regulation of Alternative Splicing in the Nervous System
• Functions of the Tau Protein beyond Microtubule Binding
• Function of the Primate-Specific Protein Saitohin
• The Role of Tau and Saitohin in Neurodegeneration

Office: S7-326
Phone: 508-856-1414
E-mail: Athena.Andreadis@umassmed.edu
Keywords: Neurobiology, Cytoskeleton, Gene Expression, Neurodegeneration, RNA Splicing

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Postdoctoral Position Available A position is available immediately to study regulation of the mammalian nervous system at the molecular level. The research will focus on mechanisms and consequences of expressing isoforms of neuronal-specific genes that arise from alternative splicing. Candidates should have a Ph. D. with experience in molecular and cellular biology; knowledge of immunological techniques is strongly desirable. Please send C. V. and the names/phone numbers/email addresses of three references. For more details, please contact Dr. Andreadis. UMMS is an Affirmative Action/Equal Opportunity Employer.