Autophagy and neurodegeneration: When the cleaning crew goes on strike

Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
The Lancet Neurology (Impact Factor: 21.82). 05/2007; 6(4):352-61. DOI: 10.1016/S1474-4422(07)70076-5
Source: PubMed

ABSTRACT Intracellular accumulation of altered and misfolded proteins is the basis of most neurodegenerative disorders. Altered proteins are usually organised in the form of toxic multimeric complexes that eventually promote neuronal death. Cells rely on surveillance mechanisms that take care of the removal of these toxic products. What then goes wrong in these pathologies? Recent studies have shown that a primary failure in autophagy, a mechanism for clearance of intracellular components in lysosomes, could be responsible for the accumulation of these altered proteins inside the affected neurons. In this Review we summarise our current knowledge on the contribution of autophagy to the maintenance of normal cellular homoeostasis, its changes in neurodegenerative disorders, and the role of aggravating factors such as oxidative stress and ageing on autophagic failure in these pathologies.

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    • "Some of these are highly conserved from flies to mammals. Failure of autophagy accumulates damaged proteins inside the cells, which are responsible for the development of different neurodegenerative disorders [16], autoimmunity [17] and cancer [18]. Similarly, growing evidence suggests that autophagy may play an important role in cellular aging [19]. "
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    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 09/2014; 1842(12). DOI:10.1016/j.bbadis.2014.09.007 · 5.09 Impact Factor
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    • "For 60 to 70 years our body's natural defenses are able to ward off disease progression. Once we reach an unknown threshold, our repair and clearance mechanisms-which slow with age-are no longer able to counteract the damage to our cells (Martinez- Vicente et al., 2005; Martinez-Vicente and Cuervo, 2007; Rattan, 2010). This slowing then results in intracellular accumulation of misfolded proteins that form toxic multimetric complexes. "
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    Frontiers in Aging Neuroscience 09/2014; 6. DOI:10.3389/fnagi.2014.00234 · 2.84 Impact Factor
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    • "Different autophagy-lysosome systems have been proposed for the degradation of α-synuclein. α-Synuclein monomers are reportedly degraded by autophagy and chaperone-mediated autophagy [33], [47]–[48]. As to the degradation of α-synuclein aggregates, some studies suggest autophagy [29], [34] but the others do not support this notion [49]. "
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    ABSTRACT: Macroautophagy (also known as autophagy) is an intracellular self-eating mechanism and has been proposed as both neuroprotective and neurodestructive in the central nervous system (CNS) neurodegenerative diseases. In the present study, the role of autophagy involving mitochondria and α-synuclein was investigated in MPP+ (1-methyl-4-phenylpyridinium)-induced oxidative injury in chloral hydrate-anesthetized rats in vivo. The oxidative mechanism underlying MPP+-induced neurotoxicity was identified by elevated lipid peroxidation and heme oxygenase-1 levels, a redox-regulated protein in MPP+-infused substantia nigra (SN). At the same time, MPP+ significantly increased LC3-II levels, a hallmark protein of autophagy. To block MPP+-induced autophagy in rat brain, Atg7siRNA was intranigrally infused 4 d prior to MPP+ infusion. Western blot assay showed that in vivo Atg7siRNA transfection not only reduced Atg7 levels in the MPP+-infused SN but attenuated MPP+-induced elevation in LC3-II levels, activation of caspase 9 and reduction in tyrosine hydroxylase levels, indicating that autophagy is pro-death. The immunostaining study demonstrated co-localization of LC3 and succinate dehydrogenase (a mitochondrial complex II) as well as LC3 and α-synuclein, suggesting that autophagy may engulf mitochondria and α-synuclein. Indeed, in vivo Atg7siRNA transfection mitigated MPP+-induced reduction in cytochrome c oxidase. In addition, MPP+-induced autophagy differentially altered the α-synuclein aggregates in the infused SN. In conclusion, autophagy plays a prodeath role in the MPP+-induced oxidative injury by sequestering mitochondria in the rat brain. Moreover, our data suggest that the benefits of autophagy depend on the levels of α-synuclein aggregates in the nigrostriatal dopaminergic system of the rat brain.
    PLoS ONE 03/2014; 9(3):e91074. DOI:10.1371/journal.pone.0091074 · 3.23 Impact Factor
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