Mitochondrial Dysfunction and Neurodegeneration in Lysosomal Storage Disorders

Plotegher, Nicoletta; Duchen, Michael R.

doi:10.1016/j.molmed.2016.12.003

Cited by 118 publications

(121 citation statements)

References 134 publications

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“…Mitochondrial impairment is a common feature of LSDs and other neurodegenerative disorders, although the mechanism involved may vary among mitochondrial fragmentation, reduction in mitochondrial respiration and membrane potential, dysregulation of mitochondrial quality control pathways and accumulation of damaged mitochondria [62]. A recent review by Plotegher and Duchen [62] summarizes all the LSDs with some forms of mitochondrial dysfunction and underlines its importance in the pathogenesis of these disease.…”

Section: Discussionmentioning

confidence: 99%

“…A recent review by Plotegher and Duchen [62] summarizes all the LSDs with some forms of mitochondrial dysfunction and underlines its importance in the pathogenesis of these disease. There can be several causes that lead to mitochondrial dysregulation: the lysosomal impairment that characterizes all LSDs, but also the oxidative stress, autophagy, calcium dyshomeostasis and the accumulation of proteins, such as those characterizing some neurodegenerative diseases (i.e., α-synuclein in Parkinson’s disease) [62]. …”

Section: Discussionmentioning

confidence: 99%

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Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model

Salvalaio

D’Avanzo

Rigon

et al. 2017

IJMS

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Lysosomal storage disorders (LSDs) are a group of about 50 genetic metabolic disorders, mainly affecting children, sharing the inability to degrade specific endolysosomal substrates. This results in failure of cellular functions in many organs, including brain that in most patients may go through progressive neurodegeneration. In this study, we analyzed the brain of the mouse model for Hunter syndrome, a LSD mostly presenting with neurological involvement. Whole transcriptome analysis of the cerebral cortex and midbrain/diencephalon/hippocampus areas was performed through RNA-seq. Genes known to be involved in several neurological functions showed a significant differential expression in the animal model for the disease compared to wild type. Among the pathways altered in both areas, axon guidance, calcium homeostasis, synapse and neuroactive ligand–receptor interaction, circadian rhythm, neuroinflammation and Wnt signaling were the most significant. Application of RNA sequencing to dissect pathogenic alterations of complex syndromes allows to photograph perturbations, both determining and determined by these disorders, which could simultaneously occur in several metabolic and biochemical pathways. Results also emphasize the common, altered pathways between neurodegenerative disorders affecting elderly and those associated with pediatric diseases of genetic origin, perhaps pointing out a general common course for neurodegeneration, independent from the primary triggering cause.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model

Salvalaio

D’Avanzo

Rigon

et al. 2017

IJMS

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“…In certain LSDs, the resultant pathology can be explained by the nature of molecules that accumulate (TABLeS 1,2). Thus, the abun dance of cerebrosides and gangliosides that deposit in the central nervous system (CNS) of patients with sphingo lipid storage disorders, such as type II (acute infantile neuronopathic) Gaucher disease, underlies the severe neurological symptoms of such disorders 67,68 . In patients with Pompe disease, which is caused by α glucosidase deficiency, the high levels of non degraded glycogen that accumulate in muscles could explain the observed myopathy 69,70 .…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

“…Alterations in several autophagy processes have also been described in LSDs. Thus, deregulated mitophagy, which results in the accu mulation of damaged mitochondria, occurs in LSDs, leading to major inflammatory consequences in specific tissues 67,72 . Perturbations in mitochondrial dynamics are frequently observed, which have been linked to the increased production of reactive oxygen species, ATP production and Ca 2+ imbalance.…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

517

374

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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“…In turn, mitochondrial cholesterol accumulation led to an increase in glycolytic flux and mitochondrial oxidative stress, linking aberrant lipid composition and transfer to metabolic alterations. More generally, there is evidence that lysosomal storage disorders, particularly lipid storage disorders, result in severe mitochondrial dysfunction including their altered morphology, calcium signaling, redox imbalance, and altered TCA cycle flux (for comprehensive review see (Plotegher and Duchen, 2017)).…”

Section: Disruption Of Lysosomal Lipid Homeostasis In Disease and Agingmentioning

confidence: 99%

Emerging Roles for the Lysosome in Lipid Metabolism

Thelen

Zoncu

2017

Trends in Cell Biology

200

156

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Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and non-vesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease.

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Mitochondrial Dysfunction and Neurodegeneration in Lysosomal Storage Disorders

Cited by 118 publications

References 134 publications

Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model

Brain RNA-Seq Profiling of the Mucopolysaccharidosis Type II Mouse Model

Lysosomes as a therapeutic target

Emerging Roles for the Lysosome in Lipid Metabolism

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