Autophagy and misfolded proteins in neurodegeneration

Metcalf, Daniel; Garcı́a-Arencibia, Moisés; Hochfeld, Warren E.; Rubinsztein, David C.

doi:10.1016/j.expneurol.2010.11.003

Cited by 114 publications

(91 citation statements)

References 92 publications

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“…Autophagy has lately received considerable attention due to its involvement in a multitude of human diseases, ranging from neurodegenerative disorders to cancer 29,30 . It is therefore important to develop reliable methods for assessing the autophagic flux in vitro.…”

Section: Mitophagy As Readout Of Autophagic Fluxmentioning

confidence: 99%

Depletion of mitochondria in mammalian cells through enforced mitophagy

et al. 2016

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Mitochondria are not only the "power-house" of the cell, but are also involved in a multitude of processes that include calcium storage, cell-cycle and cell-death. Traditional means to investigate mitochondrial importance in a given cellular process have centred upon depletion of mitochondrial DNA (mtDNA) through chemical or genetic means. While these methods severely disrupt mitochondrial electron transport chain, mtDNA-depleted cells still maintain mitochondria and many mitochondrial functions. Here, we describe a straightforward protocol to generate mammalian cell populations with low to non-detectable levels of mitochondria. Ectopic expression of the ubiquitin E3 ligase Parkin, combined with short-term mitochondrial uncoupler treatment, engages widespread mitophagy, and effectively eliminates mitochondria. In this protocol, we explain how to generate mitochondria-depleted cells and a variety of methods to confirm mitochondrial clearance. Furthermore, we describe culture conditions to maintain mitochondrial-depleted cells with minimal loss of viability for longitudinal studies. This method should prove useful to investigate the importance of mitochondria in a variety of biological processes.

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Section: Mitophagy As Readout Of Autophagic Fluxmentioning

confidence: 99%

Depletion of mitochondria in mammalian cells through enforced mitophagy

et al. 2016

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“…This acidification is essential for the activation of lysosomal enzymes, such as cathepsins or other acid hydrolases, which are responsible for proteolysis of the components in the autophagolysosome. 4 Macroautophagy has physiological roles in both health and disease. Upon nutrient deprivation, autophagy catabolizes cytoplasmic components nonselectively into building blocks, such as amino acids.…”

Section: The Basics Of Autophagymentioning

confidence: 99%

Lithium and Autophagy

Motoi

Shimada

Ishiguro

et al. 2014

ACS Chem. Neurosci.

124

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Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms, including autophagy regulation, in various neuropsychiatric conditions. In neurodegenerative diseases, lithium enhances degradation of aggregate-prone proteins, including mutated huntingtin, phosphorylated tau, and α-synuclein, and causes damaged mitochondria to degrade, while in a mouse model of cerebral ischemia and Alzheimer's disease autophagy downregulation by lithium is observed. The signaling pathway of lithium as an autophagy enhancer might be associated with the mammalian target of rapamycin (mTOR)-independent pathway, which is involved in myoinositol-1,4,5-trisphosphate (IP 3 ) in Huntington's disease and Parkinson's disease. However, the mTOR-dependent pathway might be involved in inhibiting glycogen synthase kinase-3β (GSK3β) in other diseases. Lithium's autophagy-enhancing property may contribute to the therapeutic benefit of patients with neuropsychiatric disorders.

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“…These protein aggregates are frequently associated with neurodegenerative diseases in humans. [36][37][38] Apoptosis is the major form of cell death and evolutionarily conserved from flies to humans. 39,40 Caspases are highly specific Cys-proteases and are the main effectors of apoptosis.…”

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confidence: 99%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

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Autophagy and misfolded proteins in neurodegeneration

Cited by 114 publications

References 92 publications

Depletion of mitochondria in mammalian cells through enforced mitophagy

Depletion of mitochondria in mammalian cells through enforced mitophagy

Lithium and Autophagy

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

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