Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases

Spencer, Brian; Potkar, Rewati; Trejo, Margarita; Rockenstein, Edward; Patrick, Christina; Gindi, Ryan; Adame, Anthony; Wyss‐Coray, Tony; Masliah, Eliezer

doi:10.1523/jneurosci.4390-09.2009

Cited by 552 publications

(495 citation statements)

References 68 publications

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“…Atg5 was unchanged, in contrast to, for example, adenovirus-induced autophagy (61) but similar to brains of patients and mouse models of AD and α-synucleinopathy (62). Masliah and colleagues showed that lentiviral beclin-1 overexpression reduces amyloid pathology in APP transgenic mice, as well as α-synuclein accumulation and degenerate pathology in α-synuclein overexpression models in vitro and in vivo; these data suggest a role of beclin-1 in autophagy induction and possibly targeting excess misfolded protein to the autophagy pathway (63,64). Beclin-1 was reduced in TPrP-treated neurons and in scrapie-infected brains, suggesting a deleterious exhaustion of this early player of the autophagic pathway.…”

Section: Discussionmentioning

confidence: 99%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

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

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Prion diseases are infectious and belong to the group of protein misfolding neurodegenerative diseases. In these diseases, neuronal dysfunction and death are caused by the neuronal toxicity of a particular misfolded form of their cognate protein. The ability to specifically target the toxic protein conformer or the neuronal death pathway would provide powerful therapeutic approaches to these diseases. The neurotoxic forms of the prion protein (PrP) have yet to be defined but there is evidence suggesting that at least some of them differ from infectious PrP (PrP Sc ). Herein, without making an assumption about size or conformation, we searched for toxic forms of recombinant PrP after dilution refolding, size fractionation, and systematic biological testing of all fractions. We found that the PrP species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a monomeric, highly α-helical form of PrP. TPrP caused autophagy, apoptosis, and a molecular signature remarkably similar to that observed in the brains of prion-infected animals. Interestingly, highly α-helical intermediates have been described for other amyloidogenic proteins but their biological significance remains to be established. We provide unique experimental evidence that a monomeric α-helical form of an amyloidogenic protein represents a cytotoxic species. Although toxic PrP has yet to be purified from prion-infected brains, TPrP might be the equivalent of one highly neurotoxic PrP species generated during prion replication. Because TPrP is a misfolded, highly neurotoxic form of PrP reproducing several features of prion-induced neuronal death, it constitutes a useful model to study PrP-induced neurodegenerative mechanisms.

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Section: Discussionmentioning

confidence: 99%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

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

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“…Likewise, activation of autophagy by rapamycin treatment increases clearance of a-synuclein aggregates in cells that express mutant a-synuclein 105 . The overexpression of beclin-1 ameliorates the accumulation of a-synuclein by enhancing lysosomal function and reducing the deficits in the autophagic pathway 155 . Pharmacological autophagy activation also ameliorates HD phenotype 88,123,124 .…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

The role of protein clearance mechanisms in organismal ageing and age-related diseases

2014

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“…Therefore, autophagy can prevent the emergence of neurodegenerative diseases. Indeed, autophagy protects against aggregation-prone mutant proteins in spinocerebellar ataxia, mutated forms of α-synuclein in Parkinson's disease, mutant Huntingtin in Huntington's disease, tau mutants that cause frontotemporal dementia, pathogenic intraneuronal amyloid beta in Alzheimer disease brain and polyglucosan inclusion bodies in Lafora disease [162,196,[198][199][200][201][202]. Interestingly, most of these neurodegenerative diseases are associated with decreased Beclin-1 levels, which might account for the impaired autophagic clearance.…”

Section: Autophagy In Other Diseasesmentioning

confidence: 99%

Autophagy: for better or for worse

et al. 2011

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Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.

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Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases

Abstract: Accumulation of the synaptic protein ␣-synuclein (␣-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD),

Cited by 552 publications

References 68 publications

Highly neurotoxic monomeric α-helical prion protein

Highly neurotoxic monomeric α-helical prion protein

The role of protein clearance mechanisms in organismal ageing and age-related diseases

Autophagy: for better or for worse

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