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Parkinson's disease is the second most common neurodegenerative disorder (1,2). Growing evidence indicates a causative role of misfolded forms of the protein α-synuclein in the pathogenesis of Parkinson's disease (3,4). Intraneuronal aggregates of α-synuclein occur in Lewy bodies and Lewy neurites (5), the cytopathological hallmarks of Parkinson's disease and related disorders called synucleinopathies (4). α-Synuclein has long been defined as a 'natively unfolded' monomer of about 14kDa (ref. 6) that is believed to acquire α-helical secondary structure only upon binding to lipid vesicles (7). This concept derives from the widespread use of recombinant bacterial expression protocols for in vitro studies, and of overexpression, sample heating and/or denaturing gels for cell culture and tissue studies. In contrast, we report that endogenous α-synuclein isolated and analysed under non-denaturing conditions from neuronal and non-neuronal cell lines, brain tissue and living human cells occurs in large part as a folded tetramer of about 58 kDa. Several methods, including analytical ultracentrifugation, scanning transmission electron microscopy and invitrocell crosslinking confirmed the occurrence of the tetramer. Native, cell-derived α-synuclein showed α-helical structure without lipid addition and had much greater lipid-binding capacity than the recombinant α-synuclein studied heretofore. Whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils invitro, native human tetramers underwent little or no amyloid-like aggregation. On the basis of these findings, we propose that destabilization of the helically folded tetramer precedes α-synuclein misfolding and aggregation in Parkinson's disease and other human synucleinopathies, and that small molecules that stabilize the physiological tetramer could reduce α-synuclein pathogenicity., To identify the native state of α-synuclein in cells while avoiding the potential breakdown of physiological assemblies by detergents, we initially used native gel electrophoresis. α-Synuclein is expressed endogenously in [...]

Author(s): Dennis J. Selkoe [1] One of the most satisfying moments in scientific investigation occurs when previously disparate phenomena of unclear origin are shown to arise from a common principle. [...]

Author(s): Howard L. Weiner [1]; Dennis J. Selkoe [1] Inflammation of the central nervous system (CNS) may be the result of both innate and adaptive immune responses. In Alzheimer's disease [...]

Author(s): Dominic M. Walsh [1]; Igor Klyubin [2]; Julia V. Fadeeva [1]; William K. Cullen [2]; Roger Anwyl [3]; Michael S. Wolfe [1]; Michael J. Rowan [2]; Dennis J. Selkoe [...]

It has been possible to determine the composition of the classical brain lesions in Alzheimer's disease and to identify at least four genes that make people vulnerable to this condition. This has boosted understanding of the genotype-to-phenotype relationships at the heart of inherited types of Alzheimer's disease. It is probable that, in the future, people reaching their 50s or older will be able to have a specific risk-assessment profile to establish their risk of developing Alzheimer's disease.

The exact role of the presenilins, including their function in amyloid-beta protein (A-beta) production, remains uncertain. However, it is possible that the conserved transmembrane (TM) aspartates in presenilins is needed for their functions, including their ability to mediate gamma-secretase activity. It has been established that the two presenilin-1 (PS1) transmembrane aspartates are vital for PS1 endoproteolysis and gamma-secretase activity. The presenilins may be cofactors for gamma-secretase, or they could themselves be gamma-secretases, which have some of the properties of aspartyl proteases.

The amyloid beta-peptide (A-beta) fragment that is linked to Alzheimer's disease has been identified in 4K and truncated form from cultures of primary, untransfected and beta-amyloid precursor protein-transfected brain cells. The production of A-beta in soluble form in vitro and in vivo as a part of normal metabolism shows that existing concepts of Alzheimer's disease pathology must be re-evaluated. Moreover, the new knowledge of A-beta's functions may lead to drugs that prevent or treat Alzheimer's disease by stopping the secretion of A-beta.

A study was conducted to establish genetic determinants of familial Alzheimer's disease (FAD). Cells cultured from a FAD family were found to express DNA which encode the beta-amyloid precursor protein (beta-APP) having mutations at two points. These cells produced six to eight times more of the protein found in cerebral depositions of Alzheimer's patients than in cells expressing normal beta-APP. This is one link between a FAD genotype and its well-known phenotype.

Alzheimer's disease is characterized by the progressive loss of intellectual functioning in aging humans. In Alzheimer patients three types of lesions with a filamentous, or string-like, structure occur in three areas of the brain: neurofibrillary tangles within neurons or nerve cells; plaques made of the amyloid (beta)-protein, in extracellular deposits in the brain; and amyloid (beta)-protein deposits in blood vessels in the brain. Amyloid (beta)-protein is also found as filaments in plaques and blood vessels of the brain in normal aged individuals and in individuals with Down's syndrome, an inherited condition characterized by various degrees of mental retardation. These lesions had only been found in the brain. However, this report shows that deposits of amyloid protein are present in other non-neural tissues (which are outside of the nervous system) including blood vessels of the skin, subcutaneous tissues (tissues beneath the skin) and the intestines. In these areas the amyloid deposits are diffuse, but lesions with the filamentous structure do occur in some healthy, aging individuals. The amyloid (beta)-protein was detected with a very sensitive test using an antibody molecule, a protein of the immune system that specifically recognized amyloid (beta)-protein. Amyloid (beta)-protein may be produced locally in many organs or may be made from a precursor protein that is present in the blood circulation. If a circulating form of the amyloid molecule exists, new therapeutic approaches could be designed to prevent both the deposition of the amyloid protein in the brain and the symptoms of Alzheimer's disease.

It has been established that the presenilin-1 (PS1) gene controls the unusual intramembranous proteolysis of the amyloid precursor protein (APP). It is therefore possible that PS1 could act as an unexpected target for drugs against Alzheimer's disease, an aggressive form of which is caused by mutations of the PS1 gene. Inhibition of presenilin synthesis late during ageing, when Alzheimer's disease normally begins, would avoid elimination of the vital function of presenilin proteins during development.

The development of Alzheimer's disease (AD) is associated with two genes, one present on chromosome 21 and the other on chromosome 19. Missense mutations in the beta-amyloid-precursor-protein gene, which favor production of the potentially neurotoxic A-beta fragment by the gene, cause the late-onset form of AD. A study conducted on fourteen early-onset familial AD pedigrees has identified the S182 gene, which contains five nucleotide changes in the amino-acid sequence in all the affected and some of the at-risk members of the family but not in normal subjects nor obligate escapees. The S182 protein has been identified as an integral membrane protein in which mutations may be linked to AD development.

Extracellular plaques made up of the peptide beta-amyloid found in the brains of people with Alzheimer's disease may be related to the disease symptomatically rather than causally. Ikuo Nishimoto and colleagues suggest that beta-amyloid precursor protein (APP), which gives rise to beta-amyloid, may also cause the plaques to form by controlling the heterotrimeric GTP-binding protein, G-O. However, APP's effect on other G proteins must be more fully assessed before this hypothesis can be accepted.

For years, circumstantial evidence has been accumulating to implicate beta amyloid in the pathogenesis of Alzheimer's disease (AD). Pathologists have long recognized that the development of amyloid plaques in the brain is a hallmark of AD, but it is virtually impossible to distinguish cause from effect simply by examining tissues at autopsy. However, in some families in which Alzheimer's disease is inherited as a dominant trait, a mutation has been found in the beta-amyloid precursor protein (beta-APP), suggesting that this protein is indeed directly involved in the development of the disorder. In the December 12, 1991 issue of Nature, scientists provide new evidence that beta-amyloid can cause degenerative neurological disease. The researchers used genetic engineering to develop laboratory mice that express a fragment of beta-APP in their brain cells. As these mice grow, pathological features develop that are strongly reminiscent of the changes observed in human Alzheimer's patients. This may prove to be the most successful animal model of AD to date. Such transgenic mice may also help researchers understand some of the effects of normal aging. Human beings, as well as a few other animals such as monkeys, accumulate amyloid beta/A4 protein in their brains. These accumulations have been termed ''preamyloid'' or ''diffuse'' plaques. In patients with Alzheimer's disease, such diffuse plaques are more common, and some apparently progress to a more compact form that is associated with pathological changes in the nerve fibers themselves. Alzheimer's disease may, therefore, not be distinct from the processes of normal aging, but may rather be an excessive expression of some normal aging processes. (Consumer Summary produced by Reliance Medical Information, Inc.)

Author(s): Dennis J. Selkoe Nature 426, 900-904 (2003). In this Insight Review Article, a competing interest was declared by the author that was accidentally omitted. This statement is: 'D.J.S. is [...]

Parkinson's disease is the second most common neurodegenerative disorder. Growing evidence indicates a causative role of misfolded forms of the protein ?-synuclein in the pathogenesis of Parkinson's disease. Intraneuronal aggregates of ?-synuclein occur in Lewy bodies and Lewy neurites, the cytopathological hallmarks of Parkinson's disease and related disorders called synucleinopathies. ?-Synuclein has long been defined as a 'natively unfolded' monomer of about 14?kDa (ref. 6) that is believed to acquire ?-helical secondary structure only upon binding to lipid vesicles. This concept derives from the widespread use of recombinant bacterial expression protocols for in vitro studies, and of overexpression, sample heating and/or denaturing gels for cell culture and tissue studies. In contrast, we report that endogenous ?-synuclein isolated and analysed under non-denaturing conditions from neuronal and non-neuronal cell lines, brain tissue and living human cells occurs in large part as a folded tetramer of about 58?kDa. Several methods, including analytical ultracentrifugation, scanning transmission electron microscopy and in vitro cell crosslinking confirmed the occurrence of the tetramer. Native, cell-derived ?-synuclein showed ?-helical structure without lipid addition and had much greater lipid-binding capacity than the recombinant ?-synuclein studied heretofore. Whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils in vitro, native human tetramers underwent little or no amyloid-like aggregation. On the basis of these findings, we propose that destabilization of the helically folded tetramer precedes ?-synuclein misfolding and aggregation in Parkinson's disease and other human synucleinopathies, and that small molecules that stabilize the physiological tetramer could reduce ?-synuclein pathogenicity. [ABSTRACT FROM AUTHOR]