Neurodegenerative disorders of protein aggregation

Shastry, Barkur S.

doi:10.1016/s0197-0186(02)00196-1

Cited by 163 publications

(120 citation statements)

References 60 publications

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“…A theoretical study based on the acylphosphatase protein proposed that variations that specifically perturb the rate of aggregation are located in certain regions of the protein sequence, each of which has a relatively high hydrophobicity and propensity to form ␤-sheets (40). These properties are not significantly changed in the variant SCAD proteins (PepPlot; Wisconsin Package Version 9.0, Genetics Computer Group (GCG), Madison, WI), thus we would not predict that the insoluble SCAD inclusions are ordered ␤-sheet aggregates as seen in Alzheimer's disease and in other neurodegenerative disorders (41)(42)(43)(44). Instead precipitation of the variant SCAD proteins may arise from hydrophobic interactions of incompletely folded, misfolded, or even partially folded variant SCAD proteins that are augmented during thermal stress and other environmental conditions affecting the degree and rate of intermolecular association.…”

Section: Turnover Of Wild Type and Variant Scad Enzymes In Scad-deficmentioning

confidence: 99%

Misfolding, Degradation, and Aggregation of Variant Proteins

Pedersen

Bross

Winter

et al. 2003

Journal of Biological Chemistry

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Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding, and preliminary experiments suggested that the variant protein displayed prolonged association with chaperonins and delayed formation of active enzyme. Accordingly, the molecular pathogenesis of SCAD deficiency may rely on intramitochondrial protein quality control mechanisms, including degradation and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate with mitochondrial hsp60 chaperonins; however, the variant SCAD proteins remained associated with hsp60 for prolonged periods of time. Biogenesis experiments at two temperatures revealed that some of the variant proteins (R22W, G68C, W153R, and R359C) caused severe misfolding, whereas others (R147W, G185S, and Q341H) exhibited a less severe temperaturesensitive folding defect. Based on the magnitude of in vitro defects, these SCAD proteins are characterized as folding-defective variants and mild folding variants, respectively. Pulse-chase experiments demonstrated that the variant SCAD proteins either triggered proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.

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Section: Turnover Of Wild Type and Variant Scad Enzymes In Scad-deficmentioning

confidence: 99%

Misfolding, Degradation, and Aggregation of Variant Proteins

Pedersen

Bross

Winter

et al. 2003

Journal of Biological Chemistry

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“…One such property is the aggregation of abnormal protein components leading to their selective loss in disorders such as AD (intra-and extracellular aggregation of amyloid β [Aβ], as well as intracellular aggregation of hyperphosphorylated tau protein, leading to the formation of neurofibrillary tangles (NFTs)), Parkinson's disease (PD; aggregation of α-synuclein, leading to the formation of intracellular Lewy bodies) and Huntington's disease (intracellular aggregates of huntingtin protein) [131][132][133].…”

Section: Accumulation Of Ndna Damage or Neuron Loss: Implications Formentioning

confidence: 99%

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

et al. 2008

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According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.

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“…The causative factors of various neurodegenerative disorders, such as Parkinson disease (PD), 2 Alzheimer disease, and some forms of spongiform encephalopathy, are associated with the formation of abnormally aggregated proteins (1). The aggregates, known as amyloid fibrils, are formed from proteins and peptides and are characterized by their unique fibrous appearance and ␤-rich structure (2)(3)(4).…”

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confidence: 99%

Amyloid Fibril Formation of α-Synuclein Is Accelerated by Preformed Amyloid Seeds of Other Proteins

Yagi

Kusaka

Hongo

et al. 2005

Journal of Biological Chemistry

100

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␣-Synuclein is one of the causative proteins of familial Parkinson disease, which is characterized by neuronal inclusions named Lewy bodies. Lewy bodies include not only ␣-synuclein but also aggregates of other proteins. This fact raises a question as to whether the formation of ␣-synuclein amyloid fibrils in Lewy bodies may occur via interaction with fibrils derived from different proteins. To probe this hypothesis, we investigated in vitro fibril formation of human ␣-synuclein in the presence of preformed fibril seeds of various different proteins. We used three proteins, Escherichia coli chaperonin GroES, hen lysozyme, and bovine insulin, all of which have been shown to form amyloid fibrils. Very surprisingly, the formation of ␣-synuclein amyloid fibril was accelerated markedly in the presence of preformed seeds of GroES, lysozyme, and insulin fibrils. The structural characteristics of the natively unfolded state of ␣-synuclein may allow binding to various protein particles, which in turn triggers the formation (extension) of ␣-synuclein amyloid fibrils. This finding is very important for understanding the molecular mechanism of Parkinson disease and also provides interesting implications into the mechanism of transmissible conformational diseases.

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Neurodegenerative disorders of protein aggregation

Cited by 163 publications

References 60 publications

Misfolding, Degradation, and Aggregation of Variant Proteins

Misfolding, Degradation, and Aggregation of Variant Proteins

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

Amyloid Fibril Formation of α-Synuclein Is Accelerated by Preformed Amyloid Seeds of Other Proteins

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