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The intent of this course is to teach students how to use recombinant DNA techniques for the study of neurodiseases. How are genes responsible for diseases identified and how are the functions of these genes studied? Attention is focused on those neural diseases in which significant advances have been made using these techniques, for example, Alzheimer's, Huntington's, Prion diseases, schizophrenia, depression, disorders affecting ion channels, and muscular dystrophies. Emphasis is placed on how these studies provide a useful approach to studying the mammalian nervous system by exposing the functions of genes that would be difficult to identify in other ways.

Lectures are held in the Morison Room, A106 Atrium Mudd Hall at 9:05 on Tuesday and Thursday. Discussions are on Tuesday afternoon (1:25-2:15; 2:30-3:20 & 3:35-4:25) in the Whitaker Room, 4th Floor Corson Hall. There are two scheduled holidays during the fall semester: Fall Break, 10/15 and Thanksgiving, 11/28. If classes are cancelled for any other reason it will be posted on this site if time allows. If not, it will be posted in the lecture room.

Link to: Syllabus

Link to: Discussion Readings

Link to: Lecture Readings

Click on the links below to search the archives. You can usually print the article from the web site or download a pdf file and print it later. Be sure that you click on the "full text" version on your search results page or you will get an abstract.

Journal of Neuroscience

Cell

Science

Proceedings of National Academy of Sciences, USA

Neuron

Articles from nature, nature genetics, Trends in Neuroscience and Trends in Genetics are difficult to get online. We have many of these articles linked below. Articles for lectures and discussions are listed by the number that correspond to the reading lists. If you have trouble accessing them contact Kathie Burdick (krb3@cornell.edu) .

These articles are in pdf format and require Acrobat Reader to open them. If you do not have it, click on the link below to download a free copy.

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NOTES:

Click on READINGS. The username and password remain the same. There is no difference in how you access your lecture notes. If you have any questions/problems, please e-mail Kathie (krb3@cornell.edu) asap.

THANKSGIVING, 11/28

NO CLASS

HANDOUTS

Techniques

 

LECTURES

1. Introduction

2. Techinques for the identification of a specific gene

Outline for lectures 2 & 3

3. "Shiverer" mouse model

Figures from Lecture 3, Strach and Read, 1996

4. Relationship between genotype and phenotype in diseases of myelin

5. Reversing the effects of the Shiverer gene (deletion of MBP gene)

6. Muscular dystrophies: A case study of a genetic disease in humans

7. Other mutations in the dystrophin gene and the structure and function of dystrophin

8. More about the nature of the protein interactions involving dystrophin and multiple forms of dystrophin

9. Introduction to Down's syndrome, Alzheimer's disease and again of the brain

10. Structure and processing of beta amyloid precursor protein

11. Huntington's Disease: identification and characterization of the gene

12. Huntington's Disease: The Protein Huntingtin

13. Other nucleotide expansion disorders

14. Prion Diseases

15. Inherited Prion Diseases

16. Oxidative stress: aging and neurodegenerative diseases

17. Amyotrophic lateral sclerosis

18. Parkinson's Disease

19. Introduction to Schizophrenia

20. Depression

21. Introduction and review of the classification of ion channels and neurotransmitter receptors

22. Channelopathies (slides)

READINGS

Lecture

4a. Myelin genes: getting the dosage right

4b. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon.

5a. Restoration of myelin formation by a single type of myelin basic protein in transgenic shiverer mice

5b. "Global" cell replacement is feasible via neural stem cell transplantation: Evidence from the dysmyelinated shiverer mouse brain.

6a. Complete cloning of the duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.

6b. A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient

7b. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy

8a. An alternative dystrophin transcript specific to peripheral nerve.

8b. The neurobiology of Duchenne muscular dystrophy: learning lessons from muscle?

9. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.

11a. A polymorphic DNA marker genetically linked to Huntington's disease

11b. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's Disease chromosomes

11c. Loss of normal huntingtin function: New developments in Huntingtin's disease research.

12. Deconstructing Myotonic Dystrophy

12b. Reconstructing Myotonic Dystrophy

13a. Aggregation of Huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain.

13b. Recent advances in understanding the pathogenesis of Huntingtin's disease.

15a. Deadly conformations--Protein misfolding in Prion Diseases.

15b. Prion research: the next frontiers.

16. Energetics in the pathogenesis of neurodegenerative diseases.

17a. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.

20a. A molecular and cellular theory of depression.

22a. Epilepsy genes: excitement traced to potassium channels

22b. Enhanced aggressive behavior in mice lacking 5-HT1b receptor

Discussion

3b. New knockout mice point to molecular basis of memory.

4a. Post-translational disruption of dystroglycanligand

5a. The mitochrondrion: Is it central to apoptosis?

6a. Correlative memory deficits, Ab elevation, and amyloid plaques in transgenic mice.

6b. Measuring Memory in a Mouse Model of Alzheimer's Disease

8a. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding.

9. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase

9a. Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

13a. Generalized potential of adult neural stem cells

13b. Stem cells: New excitement, persistent questions

Additional Reading List:

The following link has good illustrations of basic molecular techniques, including PCR.

http://www.rvc.ac.uk/review/DNA_1/Index.cfm

RNA Processing Section 1.4 pages 14-19 in Chapter 1 of Human Molecular Genetics, 2nd edition. Wiley-Liss 1999

Genetic Manipulation of Animals pages 491 - 507 Human Molecular Genetics, 2nd edition, Wiley-Liss 1999

Alzheimer's Disease and the Amyloid b Protein: What is the Role of Amyloid? (1996) David H. Small and Catriona A. McLean J. Neurochem 73(2):443-449. This can be found at the following URL: http://www.jneurochem.org.

Measuring Memory in a Mouse Model of Alzheimer's Disease

Faces of Mental Illness From the New York Times Magazine, October 29, 2000.

Brain Images provides a look at a variety of neurodegenerative diseases. This site was found by Ching-Yin May Chan.

Curing the Incurable by Jonathan Weiner in, The New Yorker; February 7, 2000.

The "Neurodegenerative Disease Section" Previous Cases of the Week (COW)
Case 4, CJD
Case 9, Multi-infract Dementia
Case 28, Becker's Muscular Dystrophy
Case 46, Alzheimer's Disease
Case 60, Multiple Sclerosis

These may be found at Pathology of Neurodisease

Problem Sets

Exam Answer Key

• Practice Exams
• Exam 1 key
• Exam 2 key

Discussion Group Instructions

Discussion leaders must prepare an outline of their presentation that will be handed out in class. The discussants are encouraged to select an unassigned paper to present to the class that will be chosen on the basis of adding significantly to the topic under discussion. This particular paper may not need to be discussed in the same detail as the papers in the booklet. This is left up to the discretion of the discussant.

General instructions for preparation of outline as well as presentation:

1. Typically research papers address one basic question. This question should be stated explicitly.
2. Why is this question important? These two issues are normally found in the "Introduction".
3. In the "Results", a series of questions are asked followed by the experimentation designed to answer these questions. Again, you should explicitly state these questions and outline the experiments and results. Note: In research papers, these questions may not be stated explicitly; YOU MUST.
4. You should critically assess the relationship between the questions and experiment, as well as your confidence level in the experimental results.
5. Conclusions shouldbe stated and evaluated in the context of strength of the experimental results, and address general questions which may have been raised in other areas discussed in the course.

General comments:

1. There is no substitute for early preparation.
2. Assigned papers are a guideline. There is flexibility within the topic, but you must discuss your plans with Tom Podleski before you make final decisions. Attempt to find your own interests within the assigned topic.
3. Material covered in discussion groups is required and may appear on examinations.
4. Quality of presentation and participation in discussion groups will be considered as part of your final grade.

Qualities to be looked for in presentations:

1. Effort devoted to stimulating discussion
2. Quality of presentation

a. organization

b. preparation

c. answering questions

d. quality of visual material, e.g. transparencies, power point, etc.

Student Presentations click on the links below for complete lists of presentations

1:25 Discussion Group

2:30 Discussion Group

3:35 Discussion Group