Zeroing in on the Pathogenic Form of α-Synuclein and Its Mechanism of Neurotoxicity in Parkinson's Disease

Volles, Michael J.; Lansbury, Peter T.

doi:10.1021/bi030086j

Cited by 425 publications

(335 citation statements)

References 116 publications

(193 reference statements)

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“…We propose that ␣-Syn⌬C is one of the factors that contributes to promote the pathologic transformation of ␣-Syn in brain. Overall, the level of experimental support for the involvement of ␣-Syn⌬C in ␣-synucleinopathy is similar to the other potential contributors to ␣-synucleinopathy (36,37,44,45). Thus, our study provides a strong rationale for more detailed examinations regarding the pathogenic nature of ␣-Syn⌬C.…”

Section: Discussionsupporting

confidence: 72%

“…Although the current study only examined the overt aggregation properties of ␣-Syn⌬C, peptides with the propensity to aggregate also are prone to form potentially toxic nonfibrillar oligomers (36)(37)(38). Thus, we believe it is likely that ␣-Syn⌬C also facilitates the formation of the potentially pathogenic nonfibrillar oligomers of ␣-Syn (36,37).…”

Section: Discussionmentioning

confidence: 89%

“…Thus, we believe it is likely that ␣-Syn⌬C also facilitates the formation of the potentially pathogenic nonfibrillar oligomers of ␣-Syn (36,37). In addition to influencing ␣-Syn aggregation͞ oligomerization, the C-terminal region of ␣-Syn appears to be important for the chaperone activity of ␣-Syn (39-41) and the stability of ␣-Syn (42).…”

Section: Discussionmentioning

confidence: 99%

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Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

West

Colla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

418

451

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␣-synucleinopathy ͉ mass spectrometry ͉ proteolysis ͉ Lewy body P arkinson's disease (PD) is a common progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of substantia nigra and the presence of the fibrillar cytoplasmic aggregates of ␣-synuclein (␣-Syn) in multiple brain regions (1, 2). Mutations in the ␣-Syn gene (3-7) and the abnormal aggregation of ␣-Syn are implicated in the pathogenesis of PD, and other related diseases are classified as ␣-synucleinopathies (1, 8-10). ␣-Syn is a highly conserved protein of 140 amino acids that is predominantly expressed in neurons, particularly in presynaptic terminals (11), and may have a role in synaptic plasticity and modulation of dopaminergic neurotransmission (11).Although the bulk of previous studies focused on the aggregation and the biology of the full-length ␣-Syn (␣-SynFL) (12, 13), the conspicuous presence of lower molecular mass ␣-Syn species in ␣-Syn aggregates (14, 15), and the enhanced in vitro fibril assembly of recombinant C-terminally truncated ␣-Syn (16, 17) suggests that the low-molecular mass ␣-Syn species may be of pathogenic significance. However, because postpathogenic and͞or postmortem processes could potentially generate a variety of ␣-Syn species, the significance of low-molecular mass ␣-Syn species to the development of ␣-synucleinopathy is uncertain.Herein, we demonstrate that C-terminally truncated lowmolecular mass ␣-Syn species (␣-Syn⌬C) with aggregationpromoting properties are normally generated in vivo. The expression of familial PD (FPD)-linked mutant human (Hu) ␣-Syn is associated with the higher cellular accumulation of ␣-Syn⌬C. Moreover, human cases with ␣-Syn lesions show preferential accumulation of ␣-Syn⌬C in aggregates and higher relative levels of soluble ␣-Syn⌬C. Our findings show that ␣-Syn⌬Cs are not an artifact of postpathologic processes and are likely to participate in the disease-linked aggregation of ␣-Syn. Materials and MethodsAdditional details are provided in Supporting Materials and Methods, which is published as supporting information on the PNAS web site.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

West

Colla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

418

451

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“…in AD 100 , amyotrophic lateral sclerosis (ALS) 101 , PD 102 and familial amyloidotic polyneuropathy 103 ). Neuronal losses associated with these disorders may be brought about by toxicity exerted by smaller soluble aggregates (sometimes referred to as oligomers or protofibrils).…”

Section: The In Vitro Effects Of Ecs On Amyloid Toxicitymentioning

confidence: 99%

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

2008

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The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. Keywords: Extracellular chaperones, receptor-mediated endocytosis, amyloid, protein quality control, aggregate toxicity, fibril formation word statement (for Contents list) plus graphic (note -colour version of below graphic provided separately)Newly identified abundant extracellular chaperones (ECs) may protect the body against dangerously hydrophobic proteins/peptides. This review proposes that ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. SUMMARYThe in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…in AD , ALS (Lee et al, 2002), Parkinson's disease (Volles and Lansbury 2003) and familial amyloidotic polyneuropathy (Sousa et al, 2001)). Neuronal losses associated with these disorders may be brought about by toxicity exerted by smaller soluble aggregates (sometimes referred to as oligomers or protofibrils; see section 2.2) (Chiti and Dobson 2006).…”

Section: The In Vitro Effects Of Ecs On Amyloid Toxicitymentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

show abstract

Zeroing in on the Pathogenic Form of α-Synuclein and Its Mechanism of Neurotoxicity in Parkinson's Disease

Cited by 425 publications

References 116 publications

Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

Extracellular Chaperones and Amyloids

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