Skip Navigation


Human Molecular Genetics Advance Access originally published online on February 19, 2004
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
13/suppl_1/R123    most recent
ddh093v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Singleton, A.
Right arrow Articles by Hardy, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Singleton, A.
Right arrow Articles by Hardy, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2004, Vol. 13, Review Issue 1 R123-R126
DOI: 10.1093/hmg/ddh093

The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases

Andrew Singleton, Amanda Myers and John Hardy*

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 10, Room 6C103, MSC1589, Bethesda, MD 20892, USA

Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creuzfeldt–Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia, and {alpha}-synuclein mutations cause autosomal dominant Parkinson's disease. In all these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and in these cases the whole protein is deposited. In Alzheimer's disease, mutations in APP or presenilin 1 or 2 cause autosomal dominant disease and these are the substrate and proteases, respectively, which are responsible for the production of the deposited peptide, Aß. Thus, in all cases, the mutations lead to the disease by a mechanism that involves the deposition process. We briefly review this remarkably predictable biology, but also point out that it seems sporadic forms of all these diseases are predisposed to by genetic variability at the same loci, strongly suggesting that the quantity of the normal protein produced influences risk for the sporadic forms of the disease. The evidence for this assertion is strongest in Parkinson's disease (PD), where genetic variability in {alpha}-synuclein expression affects risk of developing disease, although the oldest evidence for the notion that increased expression of normal sequence protein can lead to disease comes from the observation of Alzheimer's disease in trisomy 21 cases. From these observations, we make predictions concerning the etiology and pathogenesis of neurodegenerative diseases in general.

* To whom correspondence should be addressed. Tel: +1 3014513829; Fax: +1 3014800335; Email: hardyj{at}mail.nih.gov


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
A. M. Pittman, H.-C. Fung, and R. de Silva
Untangling the tau gene association with neurodegenerative disorders
Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R188 - R195.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
C Vollmert, O Windl, W Xiang, A Rosenberger, I Zerr, H-E Wichmann, H Bickeboller, T Illig, the KORA group, and H A Kretzschmar
Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study.
J. Med. Genet., October 1, 2006; 43(10): e53 - e53.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. Peltonen, M. Perola, J. Naukkarinen, and A. Palotie
Lessons from studying monogenic disease for common disease.
Hum. Mol. Genet., April 15, 2006; 15(suppl_1): R67 - R74.
[Full Text] [PDF]

Home page
 Sci Aging Knowl EnvironHome page
H. A. Lashuel
Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases
Sci. Aging Knowl. Environ., September 21, 2005; 2005(38): pe28 - pe28.
[Abstract] [Full Text]

Home page
 Hum Mol GenetHome page
S. Gandhi and N. W. Wood
Molecular pathogenesis of Parkinson's disease
Hum. Mol. Genet., September 15, 2005; 14(18): 2749 - 2755.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A.J. Myers, M. Kaleem, L. Marlowe, A.M. Pittman, A.J. Lees, H.C. Fung, J. Duckworth, D. Leung, A. Gibson, C.M. Morris, et al.
The H1c haplotype at the MAPT locus is associated with Alzheimer's disease
Hum. Mol. Genet., August 15, 2005; 14(16): 2399 - 2404.
[Abstract] [Full Text] [PDF]

Home page
 Sci Aging Knowl EnvironHome page
M. Leslie
The Goldilocks Genes
Sci. Aging Knowl. Environ., October 27, 2004; 2004(43): ns8 - ns8.
[Abstract] [Full Text] [PDF]

Home page
 Protein Sci.Home page
A. Jacobs, K. Hartman, T. Laue, and M. Caffrey
Sedimentation velocity studies of the high-molecular weight aggregates of the HIV gp41 ectodomain
Protein Sci., October 22, 2004; 13(10): 2811 - 2813.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
W. Li, C. Lesuisse, Y. Xu, J. C. Troncoso, D. L. Price, and M. K. Lee
Stabilization of {alpha}-Synuclein Protein with Aging and Familial Parkinson's Disease-Linked A53T Mutation
J. Neurosci., August 18, 2004; 24(33): 7400 - 7409.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.