Human Molecular Genetics Advance Access originally published online on February 19, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
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 
-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 -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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Rademakers, J. L. Eriksen, M. Baker, T. Robinson, Z. Ahmed, S. J. Lincoln, N. Finch, N. J. Rutherford, R. J. Crook, K. A. Josephs, et al. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia Hum. Mol. Genet., December 1, 2008; 17(23): 3631 - 3642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Leslie The Goldilocks Genes Sci. Aging Knowl. Environ., October 27, 2004; 2004(43): ns8 - ns8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|