Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro

Hashimoto, Makoto; Hsu, Leigh J.; Xia, Yu; Takeda, Ayako; Sisk, Abbyann; Sundsmo, Mary; Masliah, Eliezer

doi:10.1097/00001756-199903170-00011

Cited by 416 publications

(248 citation statements)

References 5 publications

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“…The incremental aggregation process of ␣-synuclein involves several modifications (misfolding, dimer and oligomer formation, and self-aggregation) and is linked to Parkinson's disease-associated mutations (5,22,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). In this study, we detected abnormal ␣-synuclein species based on their detergent solubility and electrophoretic mobility characteristics in three different systems: human DLB cortex, transgenic mice overexpressing wild type human ␣-synuclein, and a transiently transfected cell culture system.…”

Section: Discussionmentioning

confidence: 95%

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Klucken

Shin

Masliah

et al. 2004

Journal of Biological Chemistry

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479

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Aggregation and cytotoxicity of misfolded ␣-synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated ␣-synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of ␣-synuclein in an ␣-synuclein transgenic mouse model and in an in vitro model of ␣-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding ␣-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble ␣-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble ␣-synuclein species and protected cells from ␣-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated ␣-synuclein species in vivo and in vitro and protect it from ␣-synuclein-dependent toxicity.␣-Synuclein is a natively unfolded molecule that can selfaggregate to form oligomers and fibrillar intermediates (1-5) that accumulate to form Lewy bodies (LBs) 1 and Lewy neurites in neurons at risk for degeneration in Parkinson's disease and dementia with Lewy bodies (DLB) (6 -14). For the most part, these ␣-synuclein aggregates are densely compact and can be immunostained for multiple additional components including ubiquitin, synphilin-1, and heat shock proteins (HSPs), which suggests that protein misfolding or degradation is altered in cells that develop LBs. Mouse models of ␣-synuclein aggregation exist that mimic the findings in human brains and show intracellular ␣-synuclein aggregates (15-17). Aggregated ␣-synuclein molecules are less detergent-soluble, and these detergent-insoluble species of ␣-synuclein can be detected in human brain, transgenic mouse models, and in vitro models (18 -21). Although it is known that the conformation of ␣-synuclein in LBs is significantly different from that in the neuropil (22), it is unclear which conformation of ␣-synuclein contributes to inclusion formation. In addition to the formation of intracellular aggregates, ␣-synuclein is also cytotoxic. It has been postulated that ␣-synuclein oligomers found in Parkinson's disease tissue by Western blot analysis represent the toxic species (5).HSPs belong to the family of chaperone proteins and are important in both refolding misfolded proteins and directing proteins toward proteasomal degradation (23-25). HSPs can be protective in several neurodegeneration models (26 -29), and recent data in the fly model suggest that overexpression of the molecular chaperone Hsp70 protects against ␣-synuclein-induced degeneration (26, 30). Hsp70 and its related co-chaperones may be important in ␣-synuclein misfolding. In fact, sever...

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Section: Discussionmentioning

confidence: 95%

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Klucken

Shin

Masliah

et al. 2004

Journal of Biological Chemistry

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479

400

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“…Evidence of excessive oxidation is found in the brains of PD patients (106-108). Hashimoto et al (109) demonstrated that treatment of ␣-SYN with H 2 O 2 and ferrous iron in solution led to the formation of insoluble aggregates of ␣-SYN. Treatment of neuroblastoma cells engineered to overexpress A53T, A30P, and WT ␣-SYN with iron resulted in the formation of ␣-SYN aggregates, and the mutants were more susceptible (110).…”

Section: Concentrationmentioning

confidence: 99%

Lewy bodies

Shults

2006

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

401

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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“…Other possible mechanisms of iron toxicity are impaired production of metalloproteins, altered expression of proteins containing the regulatory iron responsive element (IRE) on their RNA [2], activation of microglial cells leading to inflammation [25], promotion of protein misfolding and aggregation [26][27][28] and triggering cell death by the novel iron-dependent pathway termed 'ferroptosis' [29][30][31]. Even though these processes were convincingly demonstrated in vitro and in animal studies, there is currently little direct evidence that they are causally involved in neurodegenerative processes as it occurs in humans.…”

Section: Causes and Consequences Of Cerebral Iron Accumulationmentioning

confidence: 99%

Iron chelation in the treatment of neurodegenerative diseases

Dušek

Schneider

Aaseth

2016

Journal of Trace Elements in Medicine and Biology

103

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a b s t r a c tDisturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

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Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro

Cited by 416 publications

References 5 publications

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Hsp70 Reduces α-Synuclein Aggregation and Toxicity

Lewy bodies

Iron chelation in the treatment of neurodegenerative diseases

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