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Late-Onset Neurodegenerative Diseases—The Role of Protein Insolubility

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Late-Onset Neurodegenerative Diseases—The Role of Protein Insolubility J. Anat. (2000) 196, pp. 609–616 Printed in the United Kingdom 609 Review Late-onset neurodegenerative diseases—the role of protein insolubility WILLIAM G. JOHNSON UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA (Accepted 28 September 1999) Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson’s disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha- synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way. Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases. Key words: Neurodegeneration; insoluble protein precipitation. to the basal ganglia, such as dystonic posturing, may - accompany the rapidly progressive dementia. In CJD, (Table) a form of prion protein is found in brain associated with spongiform degeneration. This protein is found Prion disorders in the most insoluble fraction of brain proteins and is Over the past decade, an increasing number of associated with proteinase K resistance and amyloid neurodegenerative diseases of adults and older people formation. If injected or ingested, this abnormal form has been associated with protein insolubility. Prion of prion protein appears to replicate the disease. This disorders are an example. In Creutzfeldt-Jakob dis- type of disease pathogenesis was regarded as highly ease (CJD), one form of prion disease, signs referable aberrant and very rare. Correspondence to Dr William Johnson, UBHC Room D431, 671 Hoes Lane, Piscataway, NJ 08854, USA. 610 W. G. Johnson 1996, 1997). Affected members of this family have Alzheimer disease and Down syndrome: beta- typical PD clinically, with Lewy bodies by neuro- amyloid, tau, and NAC proteins pathology. The only atypical features were (1) the Alzheimer disease (AD) has also been associated with average of onset was age 46 y (although there was an insoluble protein or peptide, the beta-amyloid wide variation) compared with about 59 y in idio- fragment (A-beta) of the amyloid precursor protein. pathic PD, and (2) inheritance was autosomal domi- A-beta is found in amyloid plaques in the brain of AD nant with high penetrance while idiopathic PD is patients, and a second insoluble protein, related to the sporadic or has a multifactorial inheritance pattern. tau protein, is seen in neurofibrillary tangles of Only a few PD families have alpha-synuclein muta- affected Alzheimer neurons. Similar pathology is tions. The vast majority of patients with idiopathic observed in Down syndrome, trisomy 21. Since A- PD have a normal alpha-synuclein DNA sequence, at beta does not precipitate spontaneously, other least in the coding region. proteins in amyloid plaques were studied in search of After mutations of alpha-synuclein were found to a protein that could precipitate spontaneously and act cause PD, alpha-synuclein was identified as a major as a nucleus for precipitation of other proteins such as component of Lewy bodies by immunohistochemical beta-amyloid. Digestion of amyloid plaque with staining. The Lewy body, an intraneuronal inclusion proteases and extraction yielded a peptide that was a seen in surviving dopaminergic neurons in the sub- component of the plaque but was not A-beta, i.e. the stantia nigra, is the neuropathological hallmark of ‘non-A-beta component’ of Alzheimer plaques or PD. This eosinophilic, cytoplasmic inclusion often has NAC. Cloning of the gene of which the NAC was a a dense centre surrounded by a clear area and a fragment yielded the NACP gene (NAC precursor surrounding eosinophilic ring, although other protein gene) which was identical with the synuclein morphologies can be seen. The ultrastructural ap- gene. Synuclein had previously been found in the pearance is that of matted fibrils. Over 50 proteins electric eel, torpedo, and received its name, synuclein, have been found in Lewy bodies of PD. These Lewy because it was localised in the synapse and the nucleus bodies are also seen in more widespread distribution of the neuron. Subsequently, it has been found in the in a related disorder, diffuse Lewy body disease, in synapse but not in the nucleus; however the name which dementia prominently accompanies a move- synuclein was retained. Related proteins were dis- ment disorder resembling PD. They also are seen with covered named beta- and gamma-synuclein; the typical AD pathology in the so-called Lewy body original synuclein protein became alpha-synuclein. variant of AD (Lippa et al. 1998; Takeda et al. Alpha-synuclein has been found in other neuro- 1998a, b). degenerative diseases of ageing affecting the basal ganglia and their connections, especially those Multiple system atrophy: alpha-synuclein associated with Lewy bodies: familial Parkinson disease, apparently sporadic (multifactorial) PD, Alpha-synuclein was found by immunohistochemical diffuse Lewy body disease, the Lewy body variant of staining in glial inclusions of multiple system atrophy AD, and incidental Lewy body disease, although not (MSA) (Arima et al. 1998; Gai et al. 1998; Spillantini in Lewy bodies found incidentally and not associated et al. 1998; Tu et al. 1998; Wakabayashi et al. with neuronal loss. Recently, alpha-synuclein has 1998a, b), a group of 4 clinical disorders united by the been detected in the glial cytoplasmic inclusions in neuropathological finding of microtubular tangles in oligodendroglia in multiple system atrophy (Arima oligodendroglia. In the first disorder, striatonigral et al. 1998; Gai et al. 1998; Spillantini et al. 1998; degeneration, parkinsonism without tremor is asso- Tu et al. 1998; Wakabayashi et al. 1998a, b) and in ciated with neuronal loss and gliosis in the substantia the hippocampus following ischaemia (Ishimaru et al. nigra and neostriatum. In a second variant, Shy- 1998). Drager syndrome, autonomic dysfunction is asso- ciated with loss of preganglionic sympathetic neurons in the intermediolateral horns of the spinal cord; the Parkinson disease: alpha-synuclein additional clinical features of parkinsonism, cerebellar Alpha-synuclein was implicated in PD because mu- ataxia, or amyotrophy may be associated with tation of the alpha-synuclein gene on chromosome 4 degeneration of nigral or striatal neurons, cerebellum, (4q21-23) was found to be responsible in the large or anterior horn cells. In a third disorder, olivoponto- Contursi kindred in which PD was inherited as an cerebellar atrophy, a mixture of clinical parkinsonism autosomal dominant trait (Polymeropoulos et al. and cerebellar disorder is associated with neuronal Late-onset neurodegeneration 611 Table. Late-onset neurodegenerative diseases with insoluble temporal dementia (FTD-17), progressive supra- proteins nuclear palsy, Pick disease, the parkinsonism-de- mentia complex of Guam, corticobasal degeneration, Prion protein Creutzfeldt-Jakob disease and postencephalitic parkinsonism. Gerstmann-Stra$ ussler-Scheinker disease Frontotemporal dementia is an autosomal domi- Kuru nant disorder with high penetrance that results from Fatal familial insomnia Beta-amyloid mutations (Hutton et al. 1998) affecting the tau gene Alzheimer disease on chromosome 17 (17q21-22). Besides dementia, Alzheimer disease, Lewy body variant these patients may have parkinsonism, amyotrophy, Down syndrome and abnormal behavioural features. The pathology is Alpha-synuclein Parkinson disease, autosomal dominant nonspecific involving spongiform degeneration in the Parkinson disease, sporadic (multifactorial) basal ganglia, cerebrum and anterior horn cells. Alzheimer disease Progressive supranuclear palsy (PSP), another Alzheimer disease, Lewy body variant Multiple system atrophy tauopathy, is regarded as a sporadic disorder, but Diffuse Lewy body disease there are a few reports of multiple cases in a single Incidental Lewy body disease family (de Yebenes et al. 1995;
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