Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives

Park, Jin-Sung; Davis, Ryan L.; Sue, Carolyn M.

doi:10.1007/s11910-018-0829-3

Cited by 427 publications

(340 citation statements)

References 105 publications

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“…These energy deficits are not due to lower mitochondrial numbers, but may be influenced by enhanced mitochondrial superoxide levels. Indeed, mitochondrial impairment, namely energy deficiencies and aberrant ROS signaling, has been previously linked to several neurodegenerative diseases, 35 most notably Parkinson's disease 36 but also AD and aging. [37][38][39] Our current findings are the first to show these metabolic deficits in disease relevant and human TREM2 hypomorphic microglia.…”

Section: Discussionmentioning

confidence: 99%

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

et al. 2019

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Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD.

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Section: Discussionmentioning

confidence: 99%

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

et al. 2019

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“…Mitochondrial dysfunctions have been associated with PD development and progression (Park, Davis, & Sue, 2018). MPTP, a widely used toxin for PD modeling, causes an effective inhibition of complex I respiration in dopaminergic neuron mitochondria (Meredith & Rademacher, 2011;Schober, 2004).…”

Section: Etiological Modelsmentioning

confidence: 99%

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

et al. 2020

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Parkinson's disease (PD) is an age‐related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non‐motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α‐synuclein, LRRK2, DJ‐1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α‐synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD‐like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector‐mediated transgene expression and, recently, injections of misfolded α‐synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre‐clinical PD research towards successful disease‐modifying therapy. © 2020 The Authors.

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“…; Park et al . ; Rango and Bresolin ), ALS (Nakaya and Maragkakis ) during amyloid deposition in brain tissue (Norambuena et al . ), AD (Alexiou et al .…”

Section: Kspgs Of the Cns/pnsmentioning

confidence: 99%

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance of KS‐glycodynamics and interactive capability with neuroregulatory ligands

Melrose

2019

Journal of Neurochemistry

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Compared to the other classes of glycosaminoglycans (GAGs), that is, chondroitin/dermatan sulfate, heparin/heparan sulfate and hyaluronan, keratan sulfate (KS), have the least known of its interactive properties. In the human body, the cornea and the brain are the two most abundant tissue sources of KS. Embryonic KS is synthesized as a linear poly‐N‐acetyllactosamine chain of d‐galactose‐GlcNAc repeat disaccharides which become progressively sulfated with development, sulfation of GlcNAc is more predominant than galactose. KS contains multi‐sulfated high‐charge density, monosulfated and non‐sulfated poly‐N‐acetyllactosamine regions and thus is a heterogeneous molecule in terms of chain length and charge distribution. A recent proteomics study on corneal KS demonstrated its interactivity with members of the Slit‐Robbo and Ephrin‐Ephrin receptor families and proteins which regulate Rho GTPase signaling and actin polymerization/depolymerization in neural development and differentiation. KS decorates a number of peripheral nervous system/CNS proteoglycan (PG) core proteins. The astrocyte KS‐PG abakan defines functional margins of the brain and is up‐regulated following trauma. The chondroitin sulfate/KS PG aggrecan forms perineuronal nets which are dynamic neuroprotective structures with anti‐oxidant properties and roles in neural differentiation, development and synaptic plasticity. Brain phosphacan a chondroitin sulfate, KS, HNK‐1 PG have roles in neural development and repair. The intracellular microtubule and synaptic vesicle KS‐PGs MAP1B and SV2 have roles in metabolite transport, storage, and export of neurotransmitters and cytoskeletal assembly. MAP1B has binding sites for tubulin and actin through which it promotes cytoskeletal development in growth cones and is highly expressed during neurite extension. The interactive capability of KS with neuroregulatory ligands indicate varied roles for KS‐PGs in development and regenerative neural processes.

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Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives

Cited by 427 publications

References 105 publications

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance of KS‐glycodynamics and interactive capability with neuroregulatory ligands

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