Quality Control Compartments Coming of Age

Ben‐Gedalya, Tziona; Cohen, Ehud

doi:10.1111/j.1600-0854.2012.01330.x

Cited by 31 publications

(27 citation statements)

References 72 publications

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“…In some cases, mutations in aggregate-prone proteins (␣-synuclein in PD, huntingtin in Huntington disease) cause their accumulation and are directly linked to neuronal loss (1,2). However, in most circumstances, aggregate accumulation is secondary to other neuronal defects that are not fully defined but are associated with impaired degradation pathways, mitochondrial dysfunction, and oxidative stress (1)(2)(3)25). We show here that loss of mitochondrial activity disrupts lysosomal structure and function, leading to aggregate accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1,2,4,5). As such, autophagy plays an important neuroprotective role.…”

mentioning

confidence: 99%

“…A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1,2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1,3).…”

mentioning

confidence: 99%

“…Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1,3).…”

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confidence: 99%

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Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

198

193

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Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

198

193

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“…The apparent link between GSS and failed interaction between PrP and cyclophilin B, as well as the possibility that aggresomes become sources of toxicity in late stages of life (Ben-Gedalya and Cohen, 2012), suggest that the stabilization of nascent PrP molecules in trans position by chemical chaperones could reduce the amounts of disease-causing PrP conformers, postpone the emergence of GSS in individuals who carry the P102L, or P105L or P105S mutations and slow its progression once emerged.…”

Section: Potential Clinical Applicationsmentioning

confidence: 99%

PrP-containing aggresomes are cytosolic components of an ER quality control mechanism

Dubnikov

Ben‐Gedalya

Reiner

et al. 2016

Journal of Cell Science

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Limited detoxification capacity often directs aggregation-prone, potentially hazardous, misfolded proteins to be deposited in designated cytosolic compartments known as 'aggresomes'. The roles of aggresomes as cellular quality control centers, and the cellular origin of the deposits contained within these structures, remain to be characterized. Here, we utilized the observation that the prion protein (PrP, also known as PRNP) accumulates in aggresomes following the inhibition of folding chaperones, members of the cyclophilin family, to address these questions. We found that misfolded PrP molecules must pass through the endoplasmic reticulum (ER) in order to be deposited in aggresomes, that the Golgi plays no role in this process and that cytosolic PrP species are not deposited in pre-existing aggresomes. Prior to their deposition in the aggresome, PrP molecules lose the ER localization signal and have to acquire a GPI anchor. Our discoveries indicate that PrP aggresomes are cytosolic overflow deposition centers for the ER quality control mechanisms and highlight the importance of these structures for the maintenance of protein homeostasis within the ER.

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