Protein & Peptide Letters, Volume 11, No. 3, 2004
Contents
Amyloidogenic
Proteins and Peptides Involved
in
Human Neurodegenerative Diseases
Guest
Editor: Brian M. Austen
Properties
of Neurotoxic Peptides Related to the Bri Gene Pp.207-212
Omar
El-Agnaf, Gillian Gibson, Maria Lee, Andrew Wright and Brian M. Austen
Oligomers
on the Brain: the Emerging Role of Soluble Protein Aggregates in
Neurodegeneration. Pp.213-228
Dominic
M. Walsh and Dennis J. Selkoe
a-Synuclein
and the Pathogenesis of Parkinson’s
Disease Pp.229-237
Francis
L. Martin, Sally J.M. Williamson, Katerina E. Paleologou, David Allsop, and
Omar M.A. El-Agnaf
Polyglutamine
and Neurodegeneration: Structural Aspects Pp.239-248
Laura
Masino
Experimental
Approaches to Tse Prevention Via Inhibition of Prion Formation
Pp.249-255
Galatia
Politopoulou
Induction
of Cellular Oxidative Stress by the B-Amyloid Peptide Involved In Alzheimer's
Disease Pp.257-270
Gillian
L. Gibson, David Allsop and Brian M. Austen
a-Synuclein
Aggregation Pp.271-279
Abstracts
[Back to top] Properties
of Neurotoxic Peptides Related to the Bri Gene
Omar
El-Agnaf, Gillian Gibson, Maria Lee, Andrew Wright and Brian M. Austen
Familial British
dementia, a rare autosomal dominant neurodegenerative disorder, shares features
with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary
tangles, neuronal loss,progressive dementia, but clinically presents with
additional physical defects [1,2]. A mutation in the termination codon of the
BRI gene produces a BRI precursor protein 11 amino acids longer than the
wild-type protein [3,4]. Mutant and wild-type precursor proteins both may
undergo furin cleavage between residues 243 and 244, producing a peptide of 34
amino acids in the case of ABri and 23 amino acids long in the case of the wild
type peptide. The ABri 4kDa peptide is the main component of the amyloid
deposits found in familial British dementia brains. A decamer duplication in
the 3’ region of the BRI gene originates the peptide Adan that is associated
with dementia in Familial Danish dementia (FDD), similar to BDD clinically, but
with additional hearing and eyesight loss [5] . The resulting reading frame is
extended to 277 amino acid residues, and cleavage by furin releases a peptide
of 34 residues, which is identical to Abri and WT in its N-terminal
22-residues, but contains a distinct C-terminal 10 residues composed of mainly
hydrophobic residues. Here we demonstrate that C-terminal extensions of Abri
and Adan are required to elongate initially-formed dimers to neurotoxic soluble
oligomers and fibrils. In contrast, the shorter wild-type peptide does not
aggregate under the same conditions and is not toxic. Conformational analyses
indicate triple-b-sheet structures. Soluble nonfibrillar oligomers of oxidised ABri and
reduced Adan were observed in solution (pH7.4) of peptides prior to the
appearance of mature fibrils.
[Back to top]
Oligomers on the Brain:
The Emerging Role of Soluble Protein Aggregates in Neurodegeneration.
Dominic M. Walsh and Dennis J. Selkoe
Extracellular
fibrous amyloid deposits or intracellular inclusion bodies containing abnormal
protein fibrils characterize many different neurodegenerative diseases,
including Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia with
Lewy bodies, multiple system atrophy, Huntington’s disease, and the
transmissible ‘prion’ dementias. There is strong evidence from genetic,
transgenic mouse and biochemical studies to support the idea that the
accumulation of protein aggregates in the brain plays a seminal role in the
pathogenesis of these diseases. How monomeric proteins ultimately convert to
highly polymeric deposits is unknown. However, studies employing, synthetic,
cell-derived and purified recombinant proteins suggest that amyloid proteins
first come together to form soluble low n-oligomers. Further association of
these oligomers results in higher molecular weight assemblies including
so-called ‘protofibrils’ and ‘ADDLs’ and these eventually exceed solubility
limits until, finally, they are deposited as amyloid fibrils. With particular
reference to AD and PD, we review recent evidence that soluble oligomers are
the principal pathogenic species that drive neuronal dysfunction.
[Back to top] a-Synuclein and the Pathogenesis of Parkinson’s Disease
Francis
L. Martin, Sally J.M. Williamson, Katerina E. Paleologou, David Allsop, and
Omar M.A. El-Agnaf
Lesions known as
Lewy bodies (LBs) and Lewy neurites (LNs) characterise brains of Parkinson’s
disease (PD) patients. Intracellular aggregation of a-synuclein (a-syn)
appears to play a key role in the generation of LBs andLNs. Such aggregation in
the presence of redox metals may initiate Fenton reaction-mediated generation
of reactive oxygen species (ROS). ROS thus generated may result in cytotoxic
mechanisms such as the induction of DNA single-strand breaks.
[Back to top] Polyglutamine and Neurodegeneration: Structural Aspects
Laura
Masino
Polyglutamine
(polyQ) diseases are inherited neurodegenerative disorders caused by proteins
with expanded polyQ regions. Although the pathological mechanisms of these
diseases have not yet been elucidated, the processes of protein misfolding and
aggregation seem to be a direct cause of neurodegeneration. Detailed structural
information on polyQ proteins is therefore essential in order to understand the
mechanisms underlying pathogenesis and to design therapeutic strategies. In the
past decade, several studies have investigated the structural properties of
polyQ proteins and the molecular basis of aggregation and fibre formation. The
results obtained in these studies are reviewed here.
[Back
to top] Experimental Approaches to Tse
Prevention Via Inhibition of Prion Formation
Galatia
Politopoulou
Transmissible
spongiform encepahalopathies (TSEs) are fatal diseases that damage the central
nervous system. TSEs are unique in that
they may be inherited, infectious or spontaneous. The central pathogenic agent
is thought to be a conformationally distinct form (PrPSc) of the
endogenous prion protein(PrPc), which is high in beta-sheet content
and is resistant to proteases; infectivity is thought to involve formation of
PrPSc via imprinting of abnormal conformation on the normal form of the protein
(PrPc) by seeds of PrPSc. A number of compounds found to
inhibit the conversion of PrPc to PrPSc have been
proposed as therapeutics to halt TSEs.
[Back to top] Induction of Cellular Oxidative
Stress by the b-Amyloid Peptide Involved in Alzheimer's Disease
Gillian
L. Gibson, David Allsop and Brian M. Austen
b-amyloid, the 39-43 amino acid peptide
fragment originating from amyloid precursor protein, is today, generally
accepted as the biological entity responsible for causing the debilitating
human disorder Alzheimer's disease. Understanding the exact biological effects
of b-amyloid in vitro and in vivo
is clearly important to provide therapeutic strategies for the disease. Recent in
vitro studies have focused on the production of reactive oxygen species by
aggregating b-amyloid, but the cellular effects of b-amyloid induced reactive oxygen species
production have not been fully elucidated.
[Back to top] a-Synuclein Aggregation
Angela
M. Bodles and G. Brent Irvine
a-Synuclein is a major component of Lewy bodies in Parkinson’s disease
and is found associated with several other forms of dementia. As with other
neurodegenerative diseases, the ability of a-synuclein to aggregate and form fibrillar
deposits seems central to its pathology. We have defined a sequence within the
NAC region of a-synuclein that is necessary for aggregation. Exploitation of chemically
modified analogues of this peptide may produce inhibitors of aggregation.