Genetic dissection of neurodegenerative disease

John Hardy*

Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA

Abstract

The clinical and molecular of Alzheimer's disease, Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal

degeneration, multiple system atrophy and prion disease are reviewed. The hypothesis that these diseases share pathogenic pathways to

cell death which involve either the tau or the a-synuclein proteins is propounded. The production and use of transgenic animal models of

these disease, based on the genetic ®ndings are brie¯y reviewed in the context of the development of treatments for these prevalent and

distressing disorders. q 2001 Association for Research in Nervous and Mental Disease. All rights reserved.

Keywords: Alzheimer's disease; Parkinson's disease; Pick's disease; Progressive supranuclear palsy; Corticobasal degeneration; Multiple system atrophy;

Prion disease; Genetics; Transgenics

1. Introduction

Alzheimer's disease (AD), Parkinson's disease (PD),

Lewy body disease (LBD), `Pick's' disease and frontal

temporal dementia, progressive supranuclear palsy (PSP),

prion diseases (PrD) and multiple system atrophy (MSA)

are major neurodegenerative diseases which probably

af¯ict, in total, about 3% of the population directly and

many more than that through family relationships. Over

the last 10 years, during the decade of the brain, a combina-

tion of genetic and molecular pathologic investigations has

revealed many of the etiologies of these diseases and is now

beginning to reveal the pathogenic biochemical pathways

that lead to their clinical features. Developing an under-

standing of the etiology should help in developing better

and earlier diagnoses of these diseases, and may possibly

help in developing strategies to avoid them: developing an

understanding of the pathogeneses of these diseases is a

necessary ®rst step in devising rational treatments to replace

the palliative therapies which are used at present.

Surprisingly, these genetic and pathologic investigations

have revealed that these diseases share common pathogenic

mechanisms (Table 1): this commonality may explain the

clinical and pathologic overlaps between them and may also

have implications for the development of treatments for

them.

In this review, I have the following aims.

1. To outline the clinical genetics of these disorders.

2. To discuss the pathogenic relationships between them.

3. To discuss how the genetic ®ndings are helping in devis-

ing animal models of these diseases.

This review does not cover either the triplet repeat

diseases or amyotropic lateral sclerosis.

2. Clinical genetics of neurologic disease

2.1. Early onset autosomal dominant Alzheimer's disease

Three genetic loci have been shown to be important in

causing early onset, autosomal dominant AD. The amyloid

precursor protein (APP) gene on chromosome 21 [1], the

presenilin 1 (PS1) gene on chromosome 14 [2] and the

presenilin 2 (PS2) gene on chromosome 1 [3]. Mutations

at all three loci lead to disease in a generally predictable way

and, in families with these mutations, the age of onset is

relatively constant (see below for exceptions). Nearly all the

mutations are missense mutations (replacement of one

amino acid for another). A few involve the insertion or

deletion of a single amino acid, and one involves the dele-

tion of one exon of the protein, exon 9: even this mutation,

however, does not destroy the protein's structure [4]. Two

websites cover different aspects of these gene mutations:

http://molgen-www.uia.ac.be/ADMutations/ and http://

www.alzforum.org/members/index.html. All the pathogenic

mutations in APP are in and around the amyloid (Ab) part of

the molecule which is encoded by exons 16 and 17 of the

gene [5] (Fig. 1). Typically, the age of disease onset is in the

mid-50s, the disease is fully penetrant but the age of onset is

Clinical Neuroscience Research 1 (2001) 134±141

www.elsevier.nl/locate/clires

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PII: S1566-2772(00)00013-X

* Tel.: 11-904-953-7356; fax: 11-904-953-7356.

E-mail address: hardy@mayo.edu (J. Hardy).

modulated by the apolipoprotein E genotype (see below).

For example, in one well studied family, the age of onset of

individuals with a mutation who are E3 homozygotes is 55,

whereas E4 have an onset of 45, and E2E3 heterozygotes

have an onset of 60 [6]. The phenotype of most families with

pathogenic APP mutations is that of typical AD: there are

two exceptions. First, hereditary cerebral hemorrhage with

amyloidosis, Dutch type, is caused by E693Q [7]: in this

stroke syndrome, individuals from one kindred of Dutch

descent have stroke caused by Ab deposition in the brain

blood vessels, and second the phenotype of A692G is rather

variable: some individuals in this Dutch family have a

stroke syndrome, whereas others have a more typical

Alzheimer phenotype: the pathology in this disease variant

is also unusual [8]. As far as this author is aware, no

commercial testing for APP mutations is available. The

author is reluctantly prepared to consider requests for help

in this regard.

Most of the mutations in PS1 are missense mutations to

residues conserved between PS1 and PS2 (Fig. 2). The

major exception to this rule is the PS1 D9 mutation which

deletes exon 9 and changes a residue at the splice site. For

updated mutation information visit the website referred to

above. Most PS1 mutations are fully penetrant (people with

mutation inevitably develop disease), but there are excep-

tions [9]. In addition the variant E318G is probably a poly-

morphism although it might be a risk factor allele. The

phenotype of PS1 mutations is usually with onset in the

40s, but with typical clinical features. However, a variant

with spastic paraparesis as the presenting feature, which is

associated with unusual neuropathology is well described

[10]. This is a frequent feature of the D9 mutation, but

also occurs with other mutations ([11], and unpublished

data). The age of onset in PS1 mutation families is not

affected by ApoE genotype [12]. Athena Diagnostics offers

diagnostic tests.

Few PS2 mutations have been described (Fig. 3). So far,

they are all missense mutations to residues conserved

between PS1 and PS2. The phenotype of PS2 mutations

seems to be variable: in some individuals, the age of onset

is in the 40s whereas in others, in the same family, it is in the

70s [3,13]. It may well be that there are many other PS2

mutations, but these have not been identi®ed because they

occur in cases without an obvious family history: relatively

few such cases have been sequenced. Two apparently

benign polymorphisms have been identi®ed: R62G and

R62H. No diagnostic tests are available commercially and,

given the variable phenotype, it is dif®cult to thinks of an

effective way that this could be achieved with present tech-

nology.

Mutations in these three genes explain all known cases of

J. Hardy / Clinical Neuroscience Research 1 (2001) 134±141 135

Fig. 1. Amyloid precursor protein. Pathogenic mutations in the APP gene

(in red) in relation to the sites of cleavage of this molecule. Derived from

http://www.alzforum.org with permission.

Table 1

The pathology of human neurodegenerative disease

Alzheimer's disease Plaques (Ab), tangles (tau)

and often, Lewy bodies

(a-synuclein)

Prion disease Often PrP plaques;

sometimes tangles;

sometimes Lewy bodies

FTDP-17/Pick's disease Tangles or Pick bodies

(3-repeat tau)

Parkinson's disease/Lewy

body dementia

Lewy bodies

Progressive supranuclear

palsy and corticobasal

degeneration

Tangles; mainly 4-repeat tau

Multiple system atrophy Oligodendroglial a-synuclein

inclusions

AD with clear autosomal dominant, early onset disease.

There are no pedigrees with multiple generations and

cousins affected: there are many nuclear families and

many single cases of early onset disease in which mutations

J. Hardy / Clinical Neuroscience Research 1 (2001) 134±141136

Fig. 2. Presenilin 1. Pathogenic missense mutations in the presenilin 1 protein (in red) drawn on the likely topographic representation of this molecule. Derived

from http://www.alzforum.org with permission.

Fig. 3. Presenilin 2. Pathogenic missense mutations in the presenilin 2 protein (in red) drawn on the likely topographic representation of this molecule. Derived

from http://www.alzforum.org with permission.

have not been found but these presumably re¯ect oligogenic

or gene/environment etiologies.

2.2. Late Onset Alzheimer's disease

It is clear that there is much familial clustering in late

onset AD [14]. So far, genetic analysis has only unequivo-

cally demonstrated that the Apolipoprotein E (ApoE) is a

risk factor locus for this form of the disease [15]. The

ApoE4 allele is associated with increased risk of disease

[15], and the ApoE2 allele associated, generally, with

decreased risk [16]. ApoE4 homozygotes have a greatly

increased risk of developing AD. It is likely that there are

several other genetic risk factors for developing disease, but

these have not yet been clearly identi®ed. All authorities are

agreed that ApoE testing is not accurate or speci®c enough

to be used for predictive testing: there is discussion as to

whether it may have a role as a diagnostic aid [17±19].

Apolipoprotein E testing is offered commercially by Athena

Diagnostics.

2.3. Prion diseases

Familial cases of prion disease are caused by mutations in

the prion gene [20]. Most of these are missense mutations

but some are caused by an increase in repeat length of an

octapeptide repeat [21], and there are some premature termi-

nation mutations which occur at the C-terminal of the

protein [22]. There is common polymorphism (M129V).

The occurrence of this variant in cis or trans with pathogenic

mutations can considerably alter both the phenotype and the

age at onset of disease. The phenotype can encompass

Creuzfeld±Jakob disease, Gerstmann±Straussler syndrome

and fatal familial insomnia. The website http://www.mad-

cow.org/ is a useful reference source for of this information.

No commercial company offers prion mutation screening.

Interestingly, sporadic and iatrogenic and `new variant' CJD

cases are nearly always homozygotes for the 129 poly-

morphism [23±25].

2.4. Frontal temporal dementia

Most hereditary cases of frontal temporal dementia are

caused by mutations in the tau gene [26,27] (Fig. 4), although

there is another locus on chromosome 3 [28]. Now, a large

number of tau mutations have been described. For details, see

the website http://www.alzforum.org/members/research/

tau/tau_references.html. Most of the tau mutations are fully

penetrant and fully penetrant, although there is a wide range

of phenotypes [29]. Nearly all the mutations are within the

microtubule binding domains encoded by exons 9±13. A

cluster of mutations occurs just outside exon 10 where it

affects the alternative splicing of that exon. No commercial

company offers sequencing of tau in hereditary frontal

temporal dementia. Clinicians are welcome to contact the

author if there is the suspicion of a tau mutation in family.

The term `Pick's disease' has fallen into confused use:

many cases with tau mutations would have been previously

diagnosed as Pick's disease.

J. Hardy / Clinical Neuroscience Research 1 (2001) 134±141 137

Fig. 4. Mutations in the tau gene, both in the open reading frame (A) and showing the positions which affect splicing alone at the stem loop structure (B) or

affect both splicing and the open reading frame (C).

2.5. Progressive supranuclear palsy and corticobasal

degeneration

PSP occasionally occurs in families, but no genetic

linkages have been reported. However, it is now clear that

there are two alleles of tau occurring in the general popula-

tion: H1 and H2, and that PSP is robustly associated with

homozygosity for the H1 allele [30,31]. This is not diagnos-

tically useful: approximately 50% of the general Caucasian

population are H1 homozygotes and 95% of PSP cases.

CBD shows the same genetic association (Houlden, Hutton,

Hardy, unpublished data).

2.6. Parkinson's disease and Lewy body dementia

These diseases are discussed together because they

appear to occur in the same families. Two mutations in

the a-synuclein gene have been described, A53T and

A30P (Fig. 5): the former occurs in many families of

Greek origin [32], and the latter in a single family of

German origin [33]. Both mutations appear to be reasonably

highly penetrant, but more data is needed to establish this

with certainty. The usual phenotype is PD, but in some

cases, dementia, not parkinsonism, is the predominant

feature. Alpha-synuclein sequencing has not been offered

commercially: individuals are welcome to contact the

author if there is a family in which an a-synuclein mutation

may be suspected.

Two other genetic loci have been identi®ed: one on chro-

mosome 2p [34] and the other on chromosome 4p [35].

Neither of these loci are fully penetrant and both are asso-

ciated with variable phenotypes. It is clear that there are

other genetic loci which have not yet been identi®ed

(unpublished data).

Mutations in the parkin gene cause a parkinsonism of

young onset which can be clinically dif®cult to distinguish

from Parkinson's disease [36]. These mutations appear to

always be recessive in their mode of inheritance.

3. The relationship between the etiology andpathogenesis of neurodegenerative disease

The genetic ®ndings, outlined above, ®t with the patho-

logical features summarized in Table 1 and predict several

`rules' pertaining to these diseases [37].

1. If there is an extracellular protein pathology, the primary

genetic lesion relates to that protein. In prion disease, for

example, mutations in the prion gene are pathogenic; in

AD, mutations in the APP gene are one cause of patho-

genesis and mutations in the presenilin genes appear to

act via an effect on APP processing [38]. Another exam-

ple of this `rule' is British dementia, a plaque and tangle

disease, in which the primary lesion is also in the gene

encoding the plaque protein [39].

2. In diseases with extracellular pathology, the intracellular

pathology is secondary. The occurrence of tangles and

Lewy bodies in Alzheimer and prion diseases are thus

secondary, and alternate pathologies [40,41]. It will be of

interest to determine whether British dementia cases

have Lewy bodies as well as tangles.

3. In disease with only intracellular pathology, that pathol-

ogy is primary (mutations in the tau and a-synuclein): the

J. Hardy / Clinical Neuroscience Research 1 (2001) 134±141138

Fig. 5. The sequences of the human synucleins and of mouse a-synuclein: note that the better characterized human mutations (A53T) changes the human

sequence to the rodent sequence at that residue.

presumption must be that in the cases of these diseases

without tau or a-synuclein pathology, then the primary

lesion must relate closely to these proteins, as the prese-

nilins relate to APP in AD.

4. When the primary lesion relates to one intracellular

lesion (tau/tangles or a-synuclein/Lewy bodies), then

only that lesion is formed.

These `rules' can be used to construct a diagram of

proposed biochemical relationships based on the genetics

and pathology of these diseases (Fig. 6) [37]. If this diagram

offers an approximation to the truth, it has two implications.

1. The tau/tangle and a-synuclein/Lewy body pathologies

mark alternate routes to cell death [41].

2. Since they both can be activated by both Ab and prion, it is

likely that they share common pathogenic mechanisms.

4. Modeling neurodegenerative disease in animals

A major purpose in de®ning the genetic bases of neuro-

degenerative disease is to develop the resources to enable

transgenic modeling of them, both to test theories of patho-

genesis and to test therapies upon. For reasons of cost,

transgenic mice are the usual model chosen, although the

recent successes in developing partial animal models of both

triplet repeat diseases [42,43] and of Lewy body diseases in

Drosophila offer the prospect that for some applications this

system may be surprisingly valuable.

Use of transgenic mice to model human neurodegenera-

tive disease dates from successful modeling of prion disease

using pathogenic prion alleles as transgenes [44]. This

approach has now been used successfully to model the

amyloid formation of AD using pathogenic APP alleles as

transgenes [45], and even more effectively, using both

mutant PS1 and APP transgenes [46,47] and the tangle

formation in FTDP-17 using pathogenic tau alleles [48]:

reports of successful modeling of Lewy body disease have

not yet been replicated ([49], Duff, Farrer, Hardy, unpub-

lished data). With respect to AD, none of the transgenic

mice yet examined have developed both plaque and tangle

pathology: clearly the separate development of plaque form-

ing mice and tangle forming mice illustrates that this can

now be achieved [45,48]. Determination of whether the two

pathologies interact in such mice will be an important test of

theories of pathogenesis.

From a treatment perspective, the use of these mice is

now guiding the pharmaceutical industry in their drug

development programs, and the potential development of

an Alzheimer `amyloid vaccine' represents the ®rst example

of this approach [50]. Whether this approach to the treat-

ment of neurodegenerative disease will be successful should

become clear in the next 5 years.

J. Hardy / Clinical Neuroscience Research 1 (2001) 134±141 139

Fig. 6. Summary diagram linking all the tau and synucleinopathies is one broad framework of pathogenesis: note that (for example) this scheme is concordant

both with the amyloid cascade hypothesis and with the notion that Alzheimer's disease is a tauopathy (adapted from Ref. [37]).

5. Conclusions

Though the application of molecular genetics, we have an

increasingly clear understanding of the etiology of the major

neurodegenerative diseases. Surprisingly, many of these

diseases appear to be pathogenically related to each other.

Furthermore, these genetic ®ndings allow theories of patho-

genesis to be tested in relevant transgenic animals. In addi-

tion, treatment strategies can be assessed in these animals. It

is to be hoped and expected that therapies designed on the

basis of this genetic knowledge will reach clinical practice

within the next decade.

Acknowledgements

Work in the authors laboratory was supported by the NIH

and by the Alzheimer's Association. Updated and modi®ed

from course material prepared for the American Academy

of Neurology.

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