Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice

Xie, Yong; Zhou, Bing; Lin, Meng-Hsuan; Wang, Shiwei; Foust, Kevin D.; Sheng, Zu‐Hang

doi:10.1016/j.neuron.2015.06.026

Cited by 140 publications

(149 citation statements)

References 56 publications

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“…Mutant forms of these proteins have been shown to impair mitochondria, in part through direct targeting of these organelles (16,54,55). Similarly, impaired autophagy/lysosomes cause the accumulation of defective mitochondria in several models of neurodegenerative diseases (6,56,57). Of note, this impaired autophagic clearance often occurs as the consequence of dysfunctional lysosomes (10,57,58), and mutations in lysosomal proteins lead to neurodegeneration (6,7,12).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, impaired autophagy/lysosomes cause the accumulation of defective mitochondria in several models of neurodegenerative diseases (6,56,57). Of note, this impaired autophagic clearance often occurs as the consequence of dysfunctional lysosomes (10,57,58), and mutations in lysosomal proteins lead to neurodegeneration (6,7,12). For example, mutations in lysosomal hydrolases lead to the accumulation of intracellular material and neurodegeneration (12), a group of diseases collectively referred to as lysosomal storage diseases.…”

Section: Discussionmentioning

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%

Section: Discussionmentioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

198

193

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“…The presence of damaged mitochondria is a pathological common finding in ALS MNs that may be associated to impaired autophagy-lysosomal system. Supporting this hypothesis, autophagic vacuoles engulfing damaged mitochondria have been observed along motor neuron axons in SOD1 G93A mice (Xie et al, 2015). Interestingly, the accumulation of vacuoles was linked to an altered dynein-driven retrograde transport of late endosomes, and was rescued by the overexpression of snapin which competes with SOD1 in binding dynein.…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 82%

“…Interestingly, the accumulation of vacuoles was linked to an altered dynein-driven retrograde transport of late endosomes, and was rescued by the overexpression of snapin which competes with SOD1 in binding dynein. Remarkably, this leads to MN survival and amelioration of the ALS disease phenotype in SOD1 G93A mice (Xie et al, 2015).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 96%

“…Elimination of damaged mitochondria and aggregated proteins via the autophagy was able to slow ALS progression (Crippa et al, 2010b;Fornai et al, 2008a;Hetz et al, 2009;Xie et al, 2015). On the other hand, a reduction of neuronal loss, even though without a complete rescue of the pathology, can be obtained with the autophagy inhibitor 3-MA or knocking-down ATG5 or ATG12 (Wong et al, 2011).…”

Section: Autophagy As Therapeutic Targetmentioning

confidence: 99%

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Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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Autophagy and the endo/exosomal pathways in health and disease

Papandreou

Tavernarakis

2016

Biotechnology Journal

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Cell homeostasis requires the concerted action of cellular pathways involved in degradation, trafficking and intercellular communication, which are interlinked to satisfy the cell's needs upon demand. Defects in these pathways instigate the development of several age-related pathologies, such as neurodegenerative and chronic inflammatory diseases. Autophagy is an evolutionarily conserved and tightly regulated process of degrading cellular constituents. The endosomal and vesicular trafficking pathways contribute to this regulation and share common features with the autophagic process. Recently, autophagy has been implicated in the endosome/exosome secretory pathway. Importantly, current technological advances allow the manipulation of exosomes as drug nanocarriers in pharmaceutical intervention strategies. Here, we survey emerging findings relevant to the crosstalk between autophagy and the endo/exosomal vesicular trafficking pathways. In addition, we discuss novel methodologies that have recently been developed, which allow the utilization of these pathways for targeted drug delivery in disease.

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Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice

Cited by 140 publications

References 56 publications

Loss of Mitochondrial Function Impairs Lysosomes

Loss of Mitochondrial Function Impairs Lysosomes

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Autophagy and the endo/exosomal pathways in health and disease

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