Alpha synuclein in neurodegenerative disorders: Murderer or accomplice?

Mezey, Éva; Dehejia, Anindya; Harta, G; Papp, M; Polymeropoulos, M H; Brownstein, Michael J.

doi:10.1038/nm0798-755

Cited by 182 publications

(117 citation statements)

References 17 publications

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“…In ALS, alpha-synuclein and ubiquitin accumulate in affected neurons (9,(28)(29)(30). Lithium treatment reduces the accumulation of alphasynuclein in both MN of lamina IX (SI Fig.…”

Section: Lithium Treatment Rescues Spinal Cord Mitochondria and Facilmentioning

confidence: 99%

Lithium delays progression of amyotrophic lateral sclerosis

Fornai

Longone

Cafaro

et al. 2008

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

497

458

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ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS

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“…In ALS, alpha-synuclein and ubiquitin accumulate in affected neurons (9,(28)(29)(30). Lithium treatment reduces the accumulation of alphasynuclein in both MN of lamina IX (SI Fig.…”

Section: Lithium Treatment Rescues Spinal Cord Mitochondria and Facilmentioning

confidence: 99%

Lithium delays progression of amyotrophic lateral sclerosis

Fornai

Longone

Cafaro

et al. 2008

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

497

458

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“…Cells were cultured using culture medium containing 0.5 M cycloheximide and 1 M lactacystin formation of reactive nitrogen species such as ONOO Ϫ has also been implicated (51). Growing evidence indicates that the malfunction of the ubiquitin/proteasome system is closely associated with development of a range of neurodegenerative diseases including PD (26,28). Recently, deletion or point mutations in a member of the ubiquitin protein ligase family (Parkin) were found to be associated with young onset PD, where nigral pathology is not usually associated with Lewy body formation, in several families in Japan, Germany, Turkey, and Yemen (7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, decreases in proteasomal enzyme activity as measured by trypsin-like, chymotrypsin-like, and peptidylglutamyl peptide hydrolase (PGPH) activities are found in substantia nigra in PD (24). Although the mechanisms by which mutations in Parkin induce cell death in AR-JP are far from clear, a rise in levels of abnormal proteins due to proteasomal dysfunction may induce oxidative stress, apoptosis, and formation of protein aggregates that might be cytotoxic (25)(26)(27)(28).In the present study, we investigated how overexpression of wild-type and mutant Parkin proteins (Del 3-5, T240R, and Q311X) modulates proteasomal activity, the accumulation of ubiquitinated proteins, indices of oxidative stress, nitric oxide …”

mentioning

confidence: 99%

Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Hyun¹,

Lee²,

Hattori³

et al. 2002

Journal of Biological Chemistry

162

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Mutations in Parkin (a ubiquitin protein ligase) are involved in autosomal recessive juvenile parkinsonism, but it is not known how they cause nigral cell death. We examined the effect of Parkin overexpression on cellular levels of oxidative damage, antioxidant defenses, nitric oxide production, and proteasomal enzyme activity. Increasing expression of Parkin by gene transfection in NT-2 and SK-N-MC cells led to increased proteasomal activity, decreased levels of protein carbonyls, 3-nitrotyrosine-containing proteins, and a trend to a reduction in ubiquitinated protein levels. Transfection of these cells with DNA encoding three mutant Parkins associated with autosomal recessive juvenile parkinsonism (Del 3-5, T240R, and Q311X) gave smaller increases in proteasomal activity and led to elevated levels of protein carbonyls and lipid peroxidation. Turnover of the mutant proteins was slower than that of the wild-type protein, and both could be blocked by the proteasome inhibitor, lactacystin. A rise in levels of nitrated proteins and increased levels of NO 2 ؊ /NO 3 ؊ was also observed in cells transfected with mutant Parkins, apparently because of increased levels of neuronal nitricoxide synthase. The presence of mutant Parkin in substantia nigra in juvenile parkinsonism may increase oxidative stress and nitric oxide production, sensitizing cells to death induced by other insults. Parkinson's disease (PD)1 results from degeneration of dopaminergic neurones in the substantia nigra (1). Although most cases appear sporadic and of unknown cause, oxidative stress and apoptosis are associated with disease progression (1). Consistent with this view, increased levels of oxidative damage to DNA, proteins, and lipids and decreased levels of GSH are found in substantia nigra in PD (1-5).Autosomal recessive juvenile parkinsonism (AR-JP), an early onset form of PD, is characterized by loss of tyrosine hydroxylase-immunoreactive neurones in substantia nigra pars compacta and locus ceruleus, usually without Lewy body formation (6). Various mutations (including deletion or point mutations) in the Parkin gene located on chromosome 6 (6q25.2-q27) have been found in AR-JP patients, but no clear correlations exist between types of Parkin mutations and clinical or pathologic features (7-14).Parkin has been identified as a ubiquitin-protein ligase containing 465 amino acids, which consists of a ubiquitin-like (UBL) domain in the N terminus, two ring-finger motifs (termed RING1 and RING2) flanking a Cys-rich domain, named as the in-between RING (IBR) (9, 14). An additional segment is a linker region that connects two regions of UBL and RING1-IBR-RING2 (named as the RING box). Deletional analysis of Parkin revealed that UBL and the linker region are not necessary for association with a specific E2 enzyme. In contrast, the full region of the RING box is necessary for noncovalent association with E2. Therefore, missense mutations in the RING box of Parkin in AR-JP patients have almost completely lost the specific E2-binding activity.2 Thus, ...

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“…To determine whether our compounds are effective pharmacological chaperones in stabilizing protein folding and/or preventing protein aggregation, we used α-synuclein as a representative of protein-folding-related diseases. α-Synuclein aggregation leading to the formation of Lewy bodies is the pathological hallmark of Parkinson disease (60). The mechanism of Lewy body formation is still unclear.…”

Section: Mcl-1 Binding Assaysmentioning

confidence: 99%

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Lee

Wang

et al. 2014

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

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Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient highthroughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/ inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complexdisease targets that are traditionally deemed "undruggable." chemical biology | drug discovery | helical mimetic

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Alpha synuclein in neurodegenerative disorders: Murderer or accomplice?

Cited by 182 publications

References 17 publications

Lithium delays progression of amyotrophic lateral sclerosis

Lithium delays progression of amyotrophic lateral sclerosis

Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

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