MitoPark transgenic mouse model recapitulates the gastrointestinal dysfunction and gut-microbiome changes of Parkinson’s disease

Ghaisas, Shivani; Langley, Monica R.; Palanisamy, Bharathi N.; Dutta, Somak; Narayanaswamy, Kirthi; Plummer, Paul J.; Sarkar, Satyapriya; Ay, Muhammet; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

doi:10.1016/j.neuro.2019.09.004

Cited by 34 publications

(22 citation statements)

References 51 publications

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“…The present study identified the effects of probiotics in the MitoPark PD model, which features neuronal dopamine loss caused by mitochondrial dysfunction as its characteristic pathology [31]. It has been reported the MitoPark mice can exhibit the cardinal features of PD, such as the adult onset of neurodegeneration, progressive deterioration of motor functions, GI dysfunctions, and gut microbiome changes [31,32,46]. Based on earlier studies, the decreased locomotor activity can be obviously seen at the age of 14 weeks.…”

Section: Discussionmentioning

confidence: 72%

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson’s Disease

et al. 2020

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Parkinson’s disease (PD) is one of the common long-term degenerative disorders that primarily affect motor systems. Gastrointestinal (GI) symptoms are common in individuals with PD and often present before motor symptoms. It has been found that gut dysbiosis to PD pathology is related to the severity of motor and non-motor symptoms in PD. Probiotics have been reported to have the ability to improve the symptoms related to constipation in PD patients. However, the evidence from preclinical or clinical research to verify the beneficial effects of probiotics for the motor functions in PD is still limited. An experimental PD animal model could be helpful in exploring the potential therapeutic strategy using probiotics. In the current study, we examined whether daily and long-term administration of probiotics has neuroprotective effects on nigrostriatal dopamine neurons and whether it can further alleviate the motor dysfunctions in PD mice. Transgenic MitoPark PD mice were chosen for this study and the effects of daily probiotic treatment on gait, beam balance, motor coordination, and the degeneration levels of dopaminergic neurons were identified. From the results, compared with the sham treatment group, we found that the daily administration of probiotics significantly reduced the motor impairments in gait pattern, balance function, and motor coordination. Immunohistochemically, a tyrosine hydroxylase (TH)-positive cell in the substantia nigra was significantly preserved in the probiotic-treated PD mice. These results showed that long-term administration of probiotics has neuroprotective effects on dopamine neurons and further attenuates the deterioration of motor dysfunctions in MitoPark PD mice. Our data further highlighted the promising possibility of the potential use of probiotics, which could be the relevant approach for further application on human PD subjects.

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Section: Discussionmentioning

confidence: 72%

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson’s Disease

et al. 2020

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“… Tfam loxP/loxP ; DAT-cre; Parkin −/− : no Parkin-dependent effect on mitochondrial aggregates, mitochondrial morphology, locomotion, or TH-positive cell loss in SNc. ( 163 , 164 , 166 , 235 , 236 ) PD-mito-PstI DAT promoter-driven tetracycline transactivator protein (tTA) Inducible mito-PstI exclusively in DA neurons Expression of tetracycline-sensitive mitochondria-targeted restriction enzyme, Pst I, in DA neurons Mitochondrial matrix localization—COX8A MTS Mito-targeted restriction enzyme damages mtDNA in DA neurons Neuronal phenotype: progressive degeneration of the DA population within SNc, striatal dopamine depletion, age-dependent loss of TH-positive neurons, L-DOPA reversible motor deficit. Locomotor deficits precede TH-positive cell loss.…”

Section: In Vivo Models For Proof-of-mechanism and Proof-of-mentioning

confidence: 99%

Targeting mitophagy in Parkinson's disease

Clark

Torre

Hoshikawa

et al. 2021

Journal of Biological Chemistry

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The genetics and pathophysiology of Parkinson’s disease (PD) strongly implicate mitochondria in disease aetiology. Elegant studies over the last two decades have elucidated complex molecular signaling governing the identification and removal of dysfunctional mitochondria from the cell, a process of mitochondrial quality control known as mitophagy. Mitochondrial deficits and specifically reduced mitophagy are evident in both sporadic and familial PD. Mendelian genetics attributes loss-of-function mutations in key mitophagy regulators PINK1 and Parkin to early-onset PD. Pharmacologically enhancing mitophagy and accelerating the removal of damaged mitochondria are of interest for developing a disease-modifying PD therapeutic. However, despite significant understanding of both PINK1-Parkin-dependent and -independent mitochondrial quality control pathways, the therapeutic potential of targeting mitophagy remains to be fully explored. Here, we provide a summary of the genetic evidence supporting the role for mitophagy failure as a pathogenic mechanism in PD. We assess the tractability of mitophagy pathways and prospects for drug discovery and consider intervention points for mitophagy enhancement. We explore the numerous hit molecules beginning to emerge from high-content/high-throughput screening as well as the biochemical and phenotypic assays that enabled these screens. The chemical and biological properties of these reference compounds suggest many could be used to interrogate and perturb mitochondrial biology to validate promising drug targets. Finally, we address key considerations and challenges in achieving preclinical proof-of-concept, including in vivo mitophagy reporter methodologies and disease models, as well as patient stratification and biomarker development for mitochondrial forms of the disease.

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“…However, a recent study demonstrated that, in addition to α‐synuclein, Lewy bodies also contain membranes originating from vesicles and fragmented mitochondria (Shahmoradian et al., ). Moreover, MitoPark mice recapitulate the gastrointestinal dysfunction and gut microbiome changes characteristic of early PD (Ghaisas et al., ). Therefore, perhaps, the utility of the MitoPark mice as a robust and reproducible genetic PD model with a gradually progressing dopaminergic neurodegeneration phenotype and protein inclusions is much higher than recognized.…”

Section: Genetic 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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MitoPark transgenic mouse model recapitulates the gastrointestinal dysfunction and gut-microbiome changes of Parkinson’s disease

Cited by 34 publications

References 51 publications

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson’s Disease

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson’s Disease

Targeting mitophagy in Parkinson's disease

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

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