Review of the Alpha-Synyuclein Video - For & others interested

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http://videocast.nih.gov/ram/nss051302a.ram

Neurodegenerative Diseases: What Has Alpha Synuclein Got To Do With It?

Presented: Monday, May 13, 2002

Author/Sponsor: Virginia Lee, Ph.D., University of Pennsylvania

Total Running Time: 01:14:40

You can fast forward to these time stamps to view the sections of interest.

0:01 Introduction by Dr. Kurt Fischbeck

2:08 Dr. Lee introduces alpha-synuclein and discusses a slide showing all

the known disorders believed to be caused by aggregated filamentous

proteins. Multiple System Atrophy is shown (4th from the top).

Other disorders which show aggregated filamentous proteins:

Alzheimer's Disease

ALS

Dementia with Lewy Bodies

Parkinson's Disease

Prion Diseases

Tauopathies (includes PSP and CBGD)

Trinucleotide Repeat Expansion Disorders(includes hereditary spinocerebellar

ataxia & Huntington's Disease)

She uses several terms such as " inclusions " " aggregates " " fibrils "

" filaments " and " filamentous inclusions " . These terms all refer to the

buildup of plaque in nerve cells that is seen in neurodegenerative disorders

and that are suspected as being the cause of cell death. In MSA these

plaques are known as " glial cytoplasmic inclusions " .

5:01 Outline of Presentation

- Synucleinopathies: Overview

- Assembly of alpha-synuclein filaments

- Oxidative/Nitrative damage in alpha-synucleinopathies

- Synucleinopathy models (cell culture, animal & fly models)

6:01 Defines Lewy Bodies

- brain lesions that contain filaments of alpha-synuclein

6:38 Discusses hereditary (familial) Parkinson's disease.

- Two forms of hereditary Parkinson's are due to a mutation in the

alpha-synuclein gene.

9:10 The family of synuclein protein molecules:

- alpha-synuclein was cloned in the 1980's tried to identify it's function

- alpha & beta synuclein found in the central nervous system

- gamma synuclein found in the peripheral nervous system

- symoretin found in the retina

11:25 Possible Functions of alpha-synuclein (very technical... but shows

several possible functions they are studying both in cell cultures in test

tubes (in vitro) and in mice(in vivo).

13:50 Alpha-Synucleinopathies

- List of diseases due to alpha-synuclein

- Includes MSA, PAF and REM Sleep Behaviour Disorder

15:20 Slides showing nerve cells with inclusions

16:50 Glial Cytoplasmic Inclusions and MSA mentioned

17:20 Slide of alpha-synuclein protein structure.

- Structure divided into 3 sections.

- Shows the two mutations that cause Parkinson's

- A particular region of this protein is suspected as being the cause of the

formation of the inclusion fibrils.

20:34 Results of an experiment showing how quickly fibrils formed.

21:38 What part of the alpha-synuclein protein molecule is responsible for

the filament formation?

- If they can find this they may be able to develop a therapy to counteract

the filament/aggregate formation.

(Very important!)

22:25 Comparing alpha & beta-synuclein

(Very interesting section!)

- Lewy bodies never have beta-synuclein

- Beta-synuclein does not form aggregates

- Alpha & beta synuclein are very similar but they looked at how they differ

to try to understand why alpha-synuclein causes aggregates but

beta-synuclein doesn't.

- They identified a stretch of the alpha-synuclein protein that does not

appear in the beta-synuclein protein and theorized that this could be the

part of the protein that causes aggregation.

- They made some mutant proteins and deleted the stretch of amino acids they

believed might be causing filament aggregation.

24:00 Results of the mutant protein experiments

- Chart shows beta-synuclein does not cause aggregation

- It also shows that the mutant protein they created with the stretch of

amino acids removed also does not cause fibril aggregation!

(This is very exciting!)

25:00 Can this region of the protein (peptide 71-82)make fibrils all by

itself?

- Yes, they discovered that it could!

26:10 Summary of alpha-synuclein filament assembly

26:40 Oxidative Stress in Parkinson's Disease

- Evidence suggests oxidation plays a role in the disease process in

Parkinson's.

28:20 Slide showing chemical reactions leading to formation of Nitric Oxide

and Peroxynitrite which are toxic to cells.

29:45 Review of past research describing Peroxynitrite leading to Parkinson

Neurodegeneration.

- believe that nitration and alpha-synuclein are linked in some way (very

technical)

32:00 Review of some experiments done to test whether nitration and

alpha-synuclein are linked. (very technical)

33:45 Is alpha-synuclein really nitrated in the brain?

- Tested this using brain cells of those who died with various

neurodegenerative diseases.

- Evidence of nitration was found but it's highly variable

- Showed a slide which shows similarity of the various neurodegenerative

disorders

37:00 Chart showing solubility of alpha-synuclein (very technical)

38:50 Hypothesis about the role of oxidation and nitration in formation of

alpha-synuclein fibrils (very technical)

40:40 Antibodies which can detect oxidized alpha-synuclein (used to stain

brain cells so disease pathology can be detected)

42:20 Slides showing Diffuse Lewy Body Disease and other neurodegenerative

disorders

45:50 Experiments with cultured cells to see if they can form aggregates in

the presence of other substances including dopamine, paraquat and rotenone.

47:55 Animal models of alpha-synuclein

50:00 Describes the mice that have been genetically manipulated to have

alpha-synuclein mutations... their symptoms etc.

51:00 Slides showing brain cells of the alpha-synuclein mutant mice

53:35 One strange finding is that the substantia nigra region of the mice

brains did not show cell damage. This is a mystery as to why. Other parts

of the brain seemed to show cell damage similar to humans.

55:00 More slides showing results of mouse experiments (very technical)

59:30 The mutant mice will be used to screen for drugs that could inhibit

fibrilization of alpha-synuclein (this is important to note)

59:50 Short description of Dr. Bonini's Research with the Fruit Fly

Model of

alpha-synuclein

1:02:40 HSP70 prevents dopamine cell loss in fruit fly models of parkinson's

disease

1:05:20 Summary

1:06:25 Genetic & Environmental Risk Factors of alpha-synucleinopathies

1:08:20 Acknowledgements

1:09:40 Questions