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I. DISEASES WITH PROTEIN MISFOLDING

I. DISEASES WITH PROTEIN MISFOLDING

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and undergoing cell loss depending on the protein and disease involved [1–

5] (see Table 1). The prototype is Huntington’s disease (HD) which affects

the largest number of people. Polyglutamine stretches can form particularly stable h-sheet structures, which are prone to aggregation [6–9]. First

described in transgenic mice overexpressing exon I of Huntingtin, which

contains the polyglutamine repeat [10], nuclear inclusions of Huntingtin

form in susceptible regions of the brain. The same ubiquitinated inclusions

are also found in human HD tissue when appropriate antibodies are used

[11–14]. Although the correlation of deposits with the synaptic and cell

loss of the disease pathology is imperfect, similar to the situation in

Alzheimer’s disease, their appearance is consistent with a pathway of

protein folding and translocation that leads to cell loss. Similar observations have been made and conclusions reached for types 3 and 7

spinocerebellar ataxia (SCA-3, SCA-7) and dentatorubral–palladoluysian

atrophy (DRPLA), polyglutamine repeat diseases with cerebellar pathology [15–19]. A wide variety of insoluble proteins are associated with

chronic neurodegenerative diseases (Table 2). Familial tauopathies, collectively referred to as FTDP17, are ascribed to mutations in various tau

exonic or intronic sequences that alter mRNA isoform expression, resulting in insoluble fibrillar deposits of the microtubule-associated protein tau

on human chromosome 17. Other tauopathies have been identified,

varying with respect to the brain region affected and the ratio of the

different tau gene splice products deposited [20]. Progressive supranuclear

palsy and Pick’s disease are classic late-onset tau deposition diseases

[21,22]. Tau is a conformationally ambiguous protein that does not adopt

a defined structure in solution [23]. Hyperphosphorylation of tau favors

conformational changes leading to rapid intermolecular h-sheet formation. This inhibits the microtubule-polymerizing activity of this microtubule-associated protein and leads to NFT formation [24]. The

phosphorylation of a specific sequence on tau containing T231 facilitates

binding and depletion of a prolyl isomerase, Pin1, effecting its nuclear

function [25].

Prion diseases resulting in encephalopathy can be transmitted

between individuals within species (more rarely between species) [26–28].

A conformational variant of the normal cellular protein PrPS (PrPC)

(protease-sensitive or cellular) is believed to catalyze [29] or nucleate [30–

33] conversion to the pathological form, PrPR (protease-resistant). This

highly unusual nongenetic mode of transmission of an infectious agent has

been strongly debated [29]. The observation of multiple examples of

nucleated catalysis of aberrant polymerization of protein subunits has



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Table 1 Polyglutamine (CAG Repeat) Neurodegenerative Diseases

Repeat number

Disease



Sites of pathology



Huntington’s

Striatum (medium, spiny)

disease

Spinocerebellar

Cerebellar cortex (Purkinje cells),

ataxia (SCA), type 1

brain stem

SCA2

Cerebellum, pontine nucleus, substantia

nigra

SCA3 (Machado–

Substantia nigra, globus pallidus,

Joseph disease)

pontine nucleus, cerebellar cortex

SCA6

Cerebellar and mild brain stem atrophy

SCA7

Photoreceptors and bipolar cells,

cerebellar cortex, brain stem

Motor neurons, dorsal root ganglia

Spinal and bulbar

muscular atrophy

(SBMA)

Globus pallidus, dentatorubral and

Dentatorubralsubthalamic nuclei

palladoluysian

atrophy

(DRPLA)

a



Normal Disease

11–34



Protein



Location of

disease (normal)a



36–121 Huntingtin



NI (c)



6–39



40–81



Ataxin-1



NI (n, c)



15–29



36–64



Ataxin-2



NI (c)



13–42



61–84



Ataxin-3



NI (c)



21–30 VDCCa1Asubunit

37–130 Ataxin-7



NI (memb)

NI (n)



11–34



40–62



Androgen receptor



NI (n)



7–35



49–88



Atrophin-1



NI (n)



4–18

7–17



NI, nuclear inclusions; (c), normal cytoplasmic localization; (n), normal nuclear localization; (membr), normal membrane localization.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Table 2 Neurodegenerative Diseases with Insoluble Deposits

Disease



Sites of pathology



Major protein



Deposit



Alzheimer’s disease



Neocortex, hippocampus



h Peptide; 4R, 3R tau



Multiple=system tauopathy

(familial)

Progressive supranuclear

palsy (PSP)

Corticobasal degeneration

(CBD)

Pick’s disease

Diffuse Lewy body

disease (DLB)

Parkinson’s

disease

Multiple-system

atrophy (MSA)

Amylotrophic

lateral sclerosis (ALS)

Familial ALS

Creutzfeldt–Jakob

disease (CJD)

New variant CJD

Gerstmann–Straussler–

Scheinker disease

Fatal familial insomnia

Kuru



Frontotemporal regions,

brain stem, spinal cord

Frontotemporal regions



4R tau

4R tau NF



Diffuse and senile plaques,

paired helical formation, NFT

NFT in oligodendroglia and

neurons

NFT in astrocytes and neurons



Frontotemporal regions



4R tau



NFT



Frontotemporal regions

Cerebrocortical regions,

substantia nigra

Substantia nigra, brain

nuclei

Cerebellum, striatal regions



3R tau NF

a-Synuclein



Paired helical formation, NFT

Lewy bodies and neurites



a-Synuclein



Lewy bodies and neurites



a-Synuclein



Lewy bodies and neurites



Brain stem, spinal cord



a-Synuclein



Neuronal cytoplasm



Brain stem, spinal cord



SOD1 mutants

Prion protein



Neuronal cytoplasm

Extracellular deposits



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



markedly decreased the heretical flavor of such concepts. Transmissible

protein aggregation has also been observed with [URE3], the prion form

of Ure2p, a nonchromosomal genetic element regulating nitrogen catabolism, and with [PS1], the prion form of Sup35p in Saccharomyces

cerevisiae [31,34].

The specific etiology of prion diseases in mammalian systems depends on the modified form of the protein [35], of which different variants

display distinguishable conformations [36,37]. Most forms lead to a

spongiform encephalopathy with marked neuronal cell loss in regions that

accumulate the pathogenic protease-resistant conformer of the protein.

Some of the more virulent forms of the protein expressed in Creutzfeldt–

Jakob disease (CJD) are accompanied by classical intracellular amyloid

plaques of PrPR. Although primarily recognized as a rare animal disease

(scrapie), its appearance in the English beef herd in the 1990s and its

potential for transmission to humans after a long latency caused a flurry of

interest in detection and treatment countermeasures [38].

a-Synuclein, a synaptic protein, is deposited in Lewy bodies and

Lewy neurites in Parkinson disease [39–41], in diffuse Lewy body disease

[42], and in the Lewy body variant of Alzheimer’s disease [43]. Multiplesystem atrophy is characterized by intracellular neuronal and glial asynuclein inclusions [44]. The role for a-synuclein in these diseases was

supported by the discovery of mutant forms of a-synuclein, A53T and

A30P, in familial early-onset Parkinson’s disease [40]. Like tau, a-synuclein is a conformationally ambiguous protein with little stable secondary

structure in solution [45]. a-Synuclein, but not the related h- or g-synuclein,

can polymerize in a nucleation-dependent fashion [46–48].

Lou Gehrig’s disease (amyotrophic lateral sclerosis: ALS) displays

motor neuron deposits of hyperphosphorylated neurofilament subunits in

the sporadic disease. Familial ALS, some 20% of all cases of ALS, involves

dominant superoxide dismutase SOD1 mutants that can form h-barrel

aggregates [49–51].

To this list of protein misfolding diseases can be added rare familial

amyloidoses in which the mutated proteins have the classic amyloid fibril

congophilic birefringence and cross-h-sheet structure (Table 3). Many of

these deposits have an impact on the central nervous system (TTR,

cystatin, lysozyme) as well as on other organ systems. A newly described

disease, familial British dementia, is associated with the deposition of Abri,

a 34 amino acid, 4 kDa peptide cleaved from a 277 amino acid precursor

sequence, the last 10 amino acids of which are not normally translated [52].

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Table 3 Amyloidoses Recognized by the WHO International Nomenclature

Committee on Amyloidosis

Precursor protein

Immunoglobulin light chain

Immunoglobulin heavy chain

Apo-serum amyloid A protein

Transthyretin

h2-Microglobulin

Apolipoprotein AI

Gelsolin

Lysozyme

Fibrinogen a chain

Cystatin C

h-Amyloid precursor

protein



Prion protein

Procalcitonin

Islet amyloid polypeptide

Atrial natriuretic factor

Prolactin

Insulin

Lactoferrina

a



Associated disorder

Plasma cell disorders

Plasma cell disorders

Inflammation-associated, familial

Mediterranean fever

Familial amyloidotic neuropathy,

systemic senile amyloidosis

Dialysis-associated amyloidosis

Familial amyloidotic neuropathy,

aortic amyloidosis

Familial systemic amyloidosis

Familial systemic amyloidosis

Familial systemic amyloidosis

Familial cerebral hemorrhage

with amyloidosis

Sporadic and familial

Alzheimer’s disease,

familial cerebral hemorrhage

with amyloidosis

Spongiform encephalopathies

C-cell thyroid tumors

Insulinoma, type II diabetes

Atrial amyloidosis

Prolactinomas; pituitary

amyloidosis

Iatrogenic amyloidosis

Corneal amyloidosisa



Preliminary, awaiting confirmation by WHO International Nomenclature Committee

on Amyloidosis. The term amyloidosis is reserved by the committee specifically for

extracellular protein deposits.



another rare hereditary dementing disorder resulting from point mutations

in the neuroserpin gene [53]. FENIB is marked by unique neuronal

inclusion bodies consisting primarily of abnormal aggregated neuroserpin

filaments formed by a mechanism similar to that found in other familial

diseases of serpin conformation, including emphysema and cirrhosis due to

mutant a1-antitrypsin or thromboembolytic disease in antithrombin

mutants [54].



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



The mechanisms of cell loss in these various diseases of protein

deposition may differ in detail, but the association of insoluble protein

inclusions with the pathology suggests that interventions preventing

protein misfolding and deposition may be of therapeutic utility. Alternatively, stabilization of toxic species must be avoided, since the insoluble

form of the protein is one potential strategy for reducing the exposure to

toxic, soluble forms. Approaches similar to those applied to blocking Ah

fibril formation in Alzheimer’s disease may prove fruitful with these other

proteins, possibly extending to some of the same compounds being

developed for AD. There are examples of this for prions [55–58] and for

transthyretin [59].

The purpose of this chapter is to conceptualize the shared molecular

features of protein misfolding in neurodegenerative diseases. By stressing

the commonalities, rational strategies can be devised to target similar

pathways that lead to cellular degeneration and eventually to clinical

symptoms in these diseases. This is one way to maximize the effects of

progress made for the pharmaceutically attractive (relatively large patient

base) neurodegenerative diseases such as Alzheimer’s and Parkinson’s for

application to other serious but less prevalent neurodegenerative diseases.

Such ‘‘piggyback’’ strategies may be a starting point for therapeutics that

already have the appropriate bioavailability, brain penetration, and longterm safety profile required for these applications. Similarly, nonneural

amyloid diseases and diseases with significant amyloid components such as

type II diabetes could also be approached.



II. MECHANISMS OF PROTEIN POLYMERIZATION

Protein homopolymerization is a well-studied process by which cellular

structure is dynamically regulated in response to the environment and

cellular metabolism. Actin and tubulin exist as nucleotide-dependent

(ATP and GTP, respectively) polymers (microfilaments and microtubules) that rapidly elongate and shorten in a reversible manner

regulated by binding proteins that can catalyze either polymerization

or filament shearing. Mathematical analysis of the physical chemistry

of the polymerization of these systems has defined the nucleation and

elongation processes and provided the theoretical basis for models

describing fibril assembly [60–63]. Nature has also provided evidence

that small molecules, such as plant alkaloids and fungal secondary

metabolites, are capable of modulating protein–protein interactions



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



(actin depolymerization: cytochalasin, podophylotoxin; tubulin depolymerization: vinca alkaloids; microtubule stabilization: taxol). Another

extremely physiologically important protein polymerization reaction that

has been studied quantitatively is the process of thrombin-catalyzed

fibrinogen fragmentation and assembly of fibrillar fibrin during the

clotting of blood [64–66]. The larger size of the monomeric protein units

in these polymers has simplified detection of the various intermediates

in the assembly process. Atomic level structural resolution of these relatively large proteins has been aided by use of the modulators of

polymerization [67–69].

Protein polymerization can also lead to pathological consequences.

In contrast to physiologically normal assemblies, the pathological polymers are usually poorly reversible or degradable and tend to accumulate

until they cause problems for the surrounding cells or tissue. The polymerization of mutant hemoglobin S inside the red blood cells of individuals

afflicted with sickle cell anemia occurs rapidly and is modulated by the

hemoglobin ligand 2,3-diphosphoglycerate. The mutation decreases the

stability of the deoxygenated form of the protein, leading to exposure of

hydrophobic surfaces and an increased propensity to aggregate. A model

envisioning heterogeneous nucleation along the sides of the polymer and

branching reactions in addition to the standard homogenous nucleation

observed at the ends of growing fibrils was first described for the sickle cell

hemoglobin system [70,71]. The effectiveness of hydroxyurea treatments in

reducing the severity of the sickle cell crisis is ascribed to stabilizing effects

on the mutant hemoglobin conformation [72].

Several pathological self-polymerizing systems have been biophysically characterized sufficiently to permit identification of protein or peptide

species that could serve as molecular targets in a structure–activity

relationship. These include transthyretin (TTR) [73–76], serum amyloid

A protein (SAA) [77], microtubule-associated protein tau [78–80], amylin

or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis

(AL) [83–85], polyglutamine diseases [9,86], a-synuclein [47,48] and the

Alzheimer’s h peptide [87–96]. A variety of Ah peptide assay systems

have been established at Parke-Davis to search for inhibitors of fibril

formation that could be therapeutically useful [97].

In the search for fibril formation inhibitors, the self-association to

form amyloid fibrils of the Ah peptides containing 40 and 42 amino

acids can be treated as a coupled protein folding and polymerization

process passing through multiple intermediate peptide species. The in

vitro challenge is (1) to identify the various conformational forms and



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



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