Molecular Mechanisms of Neurodegeneration

Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration

J. Hardy


Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creutzfeldt–Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia and α-synuclein mutations cause autosomal dominant Parkinson's disease. In these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and the whole protein is deposited. In Alzheimer's disease, mutations in amyloid precursor protein or in the presenilins cause autosomal dominant disease. These are the substrate and proteases responsible for the production of the deposited peptide Aβ. Thus, in all the cases, the mutations lead to the disease by a mechanism that involves the deposition process. Furthermore, sporadic forms of all these diseases are predisposed by genetic variability at the same loci, implying that the quantity of the normal protein influences the risk of this form of disease. These results show that the amount of pathogenic protein expression is a key factor in determining disease initiation. Recent work on transgenic models of these diseases is consistent with the view that there are two stages of pathogenesis: a concentration-dependent formation of a pathogenic protein oligomer followed by aggregation on to this oligomeric template by a process that is less dependent on the concentration of the protein.

  • neurodegeneration
  • permissive templating
  • prion
  • tau
  • α-synuclein


Through the application of positional cloning strategies, nearly all the genes that cause autosomal dominant dementing diseases have now been described. This statement reflects the remarkable progress since 1990, when the first dementia-causing mutation in the prion gene was described in a letter to Lancet [1]. Finding these genes has allowed us to start to dissect the pathogeneses of these devastating disorders and, surprisingly, it has suggested that many of the diseases share pathogenic mechanisms [2]. However, in general, genetic analysis has not yet allowed us to determine the aetiologies of ‘sporadic’ disease, although a little progress in this direction has been made.

The purpose of this review is 4-fold: first, to sketch the identification of the pathogenic loci in those diseases for which it is known; secondly, to describe the pathogenic mechanisms that these mutations indicate; and thirdly, to discuss the possible aetiologies and pathogeneses of the sporadic variants of these diseases. Finally, a unifying concept, ‘permissive templating’, will be suggested as a general framework by which these diseases of protein deposition can be considered.

Prion diseases

There are three forms of prion disease: autosomal dominant, which are caused by mutations in the prion gene [3], infectious, which can be caused by infection through eating prion-contaminated foods or through iatrogenic infection [4], and sporadic, of no known cause [5].

The prion gene has two common coding variants in Caucasian populations: one with prion M129 and the other with prion V129 [6,7]. It has long been recognized that homozygosity at codon 129 predisposes to sporadic disease, presumably because of the necessity of prion–prion interactions and symmetry considerations [5]. However, in addition to this well-established risk, recent genetic data have shown that the prion haplotype confers additional risk to idiopathic disease [8], suggesting that genetic variability in prion expression contributes to idiopathic disease risk. Although these genetic data do not establish whether high expressors or low expressors are more susceptible, and since prion knockout mice are completely resistant to disease [9], it is most parsimonious to expect that those who express high levels of prion protein, and are homozygotes at codon 129, are most susceptible to disease. Interestingly, while infectious disease shows the same association with allelic homozygosity, it does not show the same prion promoter association [8], suggesting that the initiation of this form of disease is largely independent of the concentration of the native protein, presumably because the initiating event is the introduction of the infecting prion isoform, and that the mechanism of pathogenesis remains largely the same and relates to prion–prion interactions.

There still remain many unanswered questions concerning the relationship between the pathogeneses of the three forms of the disease: for example, it is not clear whether the mutant form of the disease always leads to a potentially infectious disease; indeed, it is likely that it does not, since several prion mutation carriers have been blood donors. It is also not clear what proportion of sporadic disease is actually infectious in aetiology, or whether this form of the disease, sometimes or always, represents somatic mutations or stochastic protein folding events. Perhaps, the most remarkable phenomenon that remains unexplained is the conundrum of the existence of multiple strains of infecting prions [10]. Historically, the existence of strains was considered to be a strong evidence against the protein-only hypothesis, but it now seems likely that prion strains are determined by the precise structure of the prion protein and that is partly, though not completely, determined by the codon 129 polymorphism [11] (see below).

Alzheimer's disease

Three genes are involved in autosomal dominant Alzheimer's disease: the APP (amyloid precursor protein) gene and the presenilin 1 and 2 genes [12]. These are the substrate and enzymes responsible for the production of the Aβ (amyloid β) peptide [13], which is deposited in the disease. Thus Aβ, specifically Aβ42, is the initiating molecule for the disease process [14].

Early onset autosomal dominant Alzheimer's disease is rare and accounts for probably less than 1% of the total number of cases. The only established risk factor for late onset disease is the genetic variability at the apolipoprotein E locus [15]. The mechanism of apolipoprotein E's involvement in pathogenesis is not understood, but clearly involves Aβ metabolism and deposition [16]. Apolipoprotein E does not, however, account for all the familial clustering. Linkage analyses in late onset disease have suggested several other loci including chromosomes 9, 10 and 12 [17]. Despite many claims, no specific locus has been found and confirmed at any of these loci. On chromosome 21, however, a linkage peak maps above the APP gene, suggesting that although the APP sequence is normal in late onset disease, genetic variability in APP expression contributes to the risk of developing disease [18]. This suggestion, of course, is entirely consistent with the work showing that APP overexpression in trisomy 21 underlies the development of the disease in Down's syndrome [2].

Primary tauopathies

Mutations in the tau gene cause many cases of autosomal dominant frontal temporal dementia in which there is a tau pathology (FTDP-17; where FTDP stands for frontotemporal dementia with Parkinsonism). Although many cases of the disease are caused by point mutations, usually in the microtubule binding domains, many other cases are caused by mutations that lead to the constitutive inclusion of the alternately spliced exon 10 [19].

In addition to these autosomal dominant cases, there are many sporadic diseases in which tau pathology occurs, usually as tangles, but also as Pick bodies or argyrophilic grains [20]. There are two genetic haplotype clades of the tau (MAPT) gene in Caucasian populations, designated H1 and H2, which differ in intron sizes, promoter sequence and wobble bases [21]. The H1 haplotype has a frequency of 75% in Caucasians and thus the H1 homozygotes constitute 60% of such populations. However, individuals with some, at least, of the three sporadic tau diseases show a robust association with H1 homozygosity, with a frequency of H1 homozygotes being 95% [2,21]. These results clearly show that variability in either tau expression or tau splicing variability (or both) contributes to disease risk [2]. In this case, it is difficult to determine whether it is the control of splicing or control of expression which is the key variable, because it is indeed clear that many mutations that lead to Mendelian disease sometimes do so through altering alternate splicing [2,19,21].

Primary synucleinopathies

Mutations in the α-synuclein gene cause autosomal dominant Parkinson's disease, and α-synuclein is the primary component of Lewy bodies, the pathognomic feature of Parkinson's disease [22]. Genetic variability in the α-synuclein promoter contributes to the risk of sporadic Parkinson's disease [23,24], with the ‘associated’ promoter allele being a stronger promoter. Perhaps, most convincingly, triplication of the whole α-synuclein locus causes autosomal dominant Parkinson's disease/Lewy body dementia with an onset age in the fourth decade and duplication of the locus leads to disease in the fifth decade [2,25]. Thus, with Parkinson's disease, there is a clear dose relationship between synuclein expression and disease occurrence, with normal genetic variability in the promoter contributing to the risk of typical idiopathic disease and with multiplications of the locus causing Mendelian disease with an onset age determined by the precise ‘dose’. Protein studies in cell lines from affected individuals in these kindreds reveal that the amount of α-synuclein produced correlates with disease [26].

Summary and synthesis

In all the diseases summarized above, the results are consistent with the view that mutations occur, which directly leads to the deposition of the characteristic protein of the disorder. In all cases, there is evidence that the genetic variability at the normal locus contributes to the risk of the sporadic disease. In each case, the precise biology of the disease slightly complicates the picture [2]. The simplest examples are the synucleinopathies where there is a straightforward relationship between the ‘dose’ of α-synuclein and the risk of disease. In the tauopathies, genetic variability of the tau locus contributes to disease risk, but because alternate splicing is an important factor in pathogenesis, it is not possible to determine whether variability in expression, or in splicing, or both, is the important factor in determining risk. In the prion diseases, the complication comes because of the occurrence, in all populations, of two alleles of the prion protein, and the association between homozygosity and sporadic disease risk. However, in addition to this association with homozygosity, there is also an additional association with promoter (i.e. expression) variability and disease risk, in sporadic but not new variant disease (see below). Finally, in Alzheimer's disease, the complication is that the deposited peptide, Aβ42, is liberated from the C-terminal fragment of APP by the presenilins: mutations in either the enzyme or the substrate lead to autosomal dominant disease, and genetic variability in APP expression contributes to sporadic disease risk.

It is worth asking what these genetic observations suggest about the initiation of all these diseases. It suggests that the initiation of all of these diseases is determined, in part, by the concentration of the pathogenic protein. Some recent results suggest however that, after initiation, the pathogenesis is largely independent of pathogenic protein concentration and the process becomes self-propagating. Many pieces of evidence can be adduced to support this contention.

In a new variant of the Creutzfeldt–Jakob disease, prion promoter variability does not contribute to disease risk, although homozygosity is a risk factor [8]. This is presumably because disease initiation in this case is by exposure to prion protein in an infectious configuration. The remarkable biology of strain propagation, which is partly determined by host prion genotype, appears to reflect efficient templating of distinctive and different pathogenic configurations [11].

While the notion of a disease-initiation phase, which is exquisitely dependent on the concentration of the pathogenic protein, followed by a propagation phase driven by efficient templating of the native protein on to a pathogenic core that is much less dependent on the concentration of the native protein, fits easily with the notion of infectious prions; it fits less easily with our current views about the other neurodegenerative diseases. However, both the genetic similarities between prion disease and the other deposition diseases reviewed above, and recent experimental data on transgenic animals suggest that this pathogenic mechanism also applies to these diseases and that other amyloidogenic proteins may seem to be ‘infectious’ under the right circumstances [27].

The first suggestion that permissive templating may occur in Alzheimer's disease came from the observation by Baker et al. [28] that injection of extracts of Alzheimer brain into elderly marmoset brains was associated with plaque formation in these monkeys, suggesting that plaque formation in the animal had been initiated by the human material. Remarkably, this observation has recently been replicated through the injection of Alzheimer brain-derived Aβ into APP transgenic mouse brain, although synthetic Aβ was ineffective [29]. The occurrence of different ‘strains’ of Aβ with different toxic properties based on such a notion of templating has recently been reported [30]. Finally, tangle formation in overexpressing tau mice has recently been shown to continue, after a certain stage, even after tau expression was switched off, suggesting that the templating of tau on to tau filaments continued even when protein levels dropped below endogenous levels [31].

All of these diverse observations are consistent with the view that a rare, stochastic event, which is exquisitely dependent on the concentration of the pathogenic protein, causes the initiation of disease through the formation of a pathogenic template. After this event has occurred, other proteins deposit on to this template and adopt the same conformation: the latter process is efficient and much less dependent on the concentration of the protein. ‘Strains’ of prion represent alternate templates [11]. It is possible that straight and paired helical filaments of tangles similarly represent different template structures for tau, since it is notable that while tau can form either, each filament is always of one type.

This theory of permissive templating suggests that disease propagation may be difficult to stop once it has been initiated, but that preventing the spread of pathogenic templates between neurons [32] might be an effective way of preventing diseases spreading along neuronal pathways.


  • Molecular Mechanisms of Neurodegeneration: Joint Biochemical Society/Neuroscience Ireland Focused Meeting (and Satellite Symposium) held at O'Reilly Hall, University College Dublin, Republic of Ireland, 14–16 March 2005. Organized by D. Walsh (University College Dublin, Republic of Ireland), V. Campbell (Trinity College Dublin, Republic of Ireland), M. Fitzgibbon (Trinity College Dublin, Republic of Ireland), B. Irvine (Queen's University Belfast, Northern Ireland), T. Lynch (University College Dublin, Republic of Ireland), J. Johnston (Queen's University Belfast, Northern Ireland), C. O'Neill (University College Cork, Republic of Ireland) and M. Farrell (Royal College of Surgeons in Ireland, Dublin, Republic of Ireland). Edited by C. O'Neill and B. Irvine.

Abbreviations: Aβ, amyloid β; APP, amyloid precursor protein


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