Parkinson’s disease-linkedD620N VPS35knockin mice manifest tau neuropathology and dopaminergic neurodegeneration

Mutations in thevacuolar protein sorting 35 ortholog(VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson’s disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familialVPS35mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germlineD620N VPS35knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein–positive neuropathology in agedVPS35KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossingVPS35KI and null mice, our data demonstrate that a singleD620N VPS35allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.

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Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson’s disease

10.1101/2020.07.06.190025 ◽

2020 ◽

Author(s):

Megan M. Senchuk ◽

Jeremy M. Van Raamsdonk ◽

Darren J. Moore

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Late Onset ◽

Lifespan Extension ◽

Disease Manifestation ◽

Genetic Pathways ◽

Dopaminergic Neurodegeneration ◽

Age Related ◽

Increased Risk ◽

Extended Longevity

AbstractBackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD.FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

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TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761773 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xin He ◽

Yue Xie ◽

Qiongping Zheng ◽

Zeyu Zhang ◽

Shanshan Ma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Transcription Factor ◽

Dopaminergic Neurons ◽

Essential Role ◽

Dopaminergic Neurodegeneration ◽

Promising Strategy ◽

Progressive Loss ◽

Mptp Model

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

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Strain- and age-dependent features of the nigro-striatal circuit in three common laboratory mouse strains, C57BL/6J, A/J, and DBA/2J - Implications for Parkinson’s disease modeling

10.1101/2020.11.30.404293 ◽

2020 ◽

Author(s):

Mélanie H. Thomas ◽

Mona Karout ◽

Beatriz Pardo Rodriguez ◽

Yujuan Gui ◽

Christian Jaeger ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Brain ◽

Dopaminergic Neurons ◽

Mouse Strains ◽

List Type ◽

Background Strain ◽

Age Related ◽

Health And Disease ◽

Over Time

AbstractMouse models have been instrumental in understanding genetic determinants of aging and its crucial role in neurodegenerative diseases. However, few studies have analyzed the evolution of the mouse brain over time at baseline. Furthermore, mouse brain studies are commonly conducted on the C57BL/6 strain, limiting the analysis to a specific genetic background. In Parkinson’s disease, the gradual demise of nigral dopaminergic neurons mainly contributes to the motor symptoms. Interestingly, a decline of the dopaminergic neuron function and integrity is also a characteristic of physiological aging in some species. Age-related nigro-striatal features have never been studied in mice of different genetic backgrounds. In this study, we analyze the morphological features in the striatum of three common mouse strains, C57BL/6J, A/J, and DBA/2J at 3-, 9- and 15 months of age. By measuring dopaminergic markers, we uncover age-related changes that differ between strains and evolve dynamically over time. Overall, our results highlight the importance of considering background strain and age when studying the murine nigro-striatal circuit in health and disease.HighlightsStudy of the integrity of the nigro-striatal circuit in C57BL/6J, A/J, and DBA/2J at different agesAge related evolution of essential features of nigral dopaminergic neurons differ between strainsConsider background strain and age is crutial to study the nigrostriatal circuit in health and disease

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Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21103459 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3459 ◽

Cited By ~ 2

Author(s):

Sandra Barata-Antunes ◽

Fábio G. Teixeira ◽

Bárbara Mendes-Pinheiro ◽

Ana V. Domingues ◽

Helena Vilaça-Faria ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Welfare ◽

Neurodegenerative Disorder ◽

Negative Impact ◽

Substantia Nigra Pars Compacta ◽

Nigrostriatal Pathway ◽

Aged Rats ◽

Age Related ◽

The Impact

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been developed not only to better understand the mechanisms underlying neurodegeneration but also to test the potential of emerging disease-modifying therapies. However, despite aging being the main risk factor for developing idiopathic PD, most of the studies do not use aged animals. Therefore, this study aimed at assessing the effect of aging in the unilateral 6-hydroxydopamine (6-OHDA)-induced animal model of PD. For this, female young adult and aged rats received a unilateral injection of 6-OHDA into the medial forebrain bundle. Subsequently, the impact of aging on 6-OHDA-induced effects on animal welfare, motor performance, and nigrostriatal integrity were assessed. The results showed that aging had a negative impact on animal welfare after surgery. Furthermore, 6-OHDA-induced impairments on skilled motor function were significantly higher in aged rats when compared with their younger counterparts. Nigrostriatal histological analysis further revealed an increased 6-OHDA-induced dopaminergic cell loss in the SNpc of aged animals when compared to young animals. Overall, our results demonstrate a higher susceptibility of aged animals to 6-OHDA toxic insult.

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Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP-Induced Parkinson’s Disease Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21218129 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8129

Author(s):

Hyunjun Park ◽

Keun-A Chang

Keyword(s):

Parkinson’S Disease ◽

Stem Cells ◽

Parkinson's Disease ◽

Neurodegenerative Disease ◽

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Therapeutic Potential ◽

Adipose Derived Stem Cells ◽

Nigrostriatal Pathway

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is clinically and pathologically characterized by motor dysfunction and the loss of dopaminergic neurons in the substantia nigra, respectively. PD treatment with stem cells has long been studied by researchers; however, no adequate treatment strategy has been established. The results of studies so far have suggested that stem cell transplantation can be an effective treatment for PD. However, PD is a progressively deteriorating neurodegenerative disease that requires long-term treatment, and this has been insufficiently studied. Thus, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASC) for repeated vein transplantation over long-term in an animal model of PD. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice, hASCs were administered on the tail vein six times at two-week intervals. After the last injection of hASCs, motor function significantly improved. The number of dopaminergic neurons present in the nigrostriatal pathway was recovered using hASC transplantation. Moreover, the administration of hASC restored altered dopamine transporter expression and increased neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), in the striatum. Overall, this study suggests that repeated intravenous transplantation of hASC may exert therapeutic effects on PD by restoring BDNF and GDNF expressions, protecting dopaminergic neurons, and maintaining the nigrostriatal pathway.

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Rare VPS35 A320V Variant in Taiwanese Parkinson’s Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology

Brain Sciences ◽

10.3390/brainsci10110783 ◽

2020 ◽

Vol 10 (11) ◽

pp. 783

Author(s):

Yih-Ru Wu ◽

Chih-Hsin Lin ◽

Chih-Ying Chao ◽

Chia-Wen Chang ◽

Chiung-Mei Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Variants ◽

Late Onset ◽

Mitochondrial Morphology ◽

Mitofusin 2 ◽

Ubiquitin Protein Ligase ◽

Vacuolar Protein ◽

Cdna Fragments ◽

Normal Controls

Sequence variants in vacuolar protein sorting 35 (VPS35) have been reported to be associated with Parkinson’s disease (PD). To investigate if the genetic variants in VPS35 contribute to Taiwanese PD, VPS35 cDNA fragments from 62 patients with PD were sequenced. A cohort of PD (n = 560) and ethnically matched controls (n = 506) were further examined for the identified mutation. The effects of the mutation on cation-independent mannose-6-phosphate receptor (CI-MPR) sorting and mitochondrial morphology were further examined in 293T cells expressing the mutant VPS35. Here, a novel heterozygous A320V in the VPS35 gene was identified in two late-onset PD (LOPD) patients, which was absent in 506 normal controls. Expression of the A320V mutant in 293T cells demonstrated increased colocalization of VPS35 with CI-MPR and decreased CI-MPR and lysosomal-associated membrane protein 2 (LAMP2) levels. Decreased CI-MPR manifested in missorting of cathepsin D and decreased proteolysis of α-synuclein. A320V mutation also increased mitochondrial E3 ubiquitin protein ligase 1 (MUL1) and thus led to mitofusin 2 (MFN2) degradation. The results suggest that the expression of VPS35 A320V leads to disrupted CI-MPR sorting and impaired mitochondrial morphology, which may partly explain its action in PD.

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Protein stability and aggregation in Parkinson's disease

Biochemical Journal ◽

10.1042/bj20080295 ◽

2008 ◽

Vol 413 (1) ◽

pp. 1-13 ◽

Cited By ~ 28

Author(s):

Philip A. Robinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Clinical Symptoms ◽

Disease Process ◽

Substantia Nigra Pars Compacta ◽

Mitochondrial Activity ◽

Apparent Paradox ◽

Lewy Neurites ◽

Age Related

Parkinson's disease (PD), the second most common age-related neurodegenerative disease, results in abnormalities in motor functioning. Many fundamental questions regarding its aetiology remain unanswered. Pathologically, it is not until 70–80% of the dopaminergic neurons from the substantia nigra pars compacta are lost before clinical symptoms are observed. Thus research into PD is complicated by this apparent paradox in that what appears to be the beginning of the disease at the clinical level is really the end point neurochemically. Consequently, we can only second guess when the disease started and what initiated it. The causation is probably complex, with contributions from both genetic and environmental factors. Intracellular proteinaceous inclusions, Lewy bodies and Lewy neurites, found in surviving dopaminergic neurons, are the key pathological characteristic of PD. Their presence points to an inability within these terminally differentiated cells to deal with aggregating proteins. Recent advances in our knowledge of the underlying disease process have come about from studies on models based on genes associated with rare hereditary forms of PD, and mitochondrial toxins that mimic the behavioural effects of PD. The reason that dopaminergic neurons are particularly sensitive may be due to the additional cellular stress caused by the breakdown of the inherently chemically unstable neurotransmitter, dopamine. In the present review, I discuss the proposal that in sporadic disease, interlinked problems of protein processing and inappropriate mitochondrial activity seed the foundation for age-related increased levels of protein damage, and a reduced ability to deal with the damage, leading to inclusion formation and, ultimately, cell toxicity.

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Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration

Science Signaling ◽

10.1126/scisignal.abg3555 ◽

2021 ◽

Vol 14 (693) ◽

pp. eabg3555

Author(s):

Qinfang Liu ◽

Judith Bautista-Gomez ◽

Daniel A. Higgins ◽

Jianzhong Yu ◽

Yulan Xiong

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Adaptor Protein ◽

Endocytic Trafficking ◽

Dopaminergic Neurodegeneration ◽

Lrrk2 G2019s ◽

Endocytic Machinery ◽

Mutant Lrrk2 ◽

The Brain

Mutations in the kinase LRRK2 and impaired endocytic trafficking are both implicated in the pathogenesis of Parkinson’s disease (PD). Expression of the PD-associated LRRK2 mutant in mouse dopaminergic neurons was shown to disrupt clathrin-mediated endocytic trafficking. Here, we explored the molecular mechanism linking LRRK2 to endocytosis and found that LRRK2 bound to and phosphorylated the μ2 subunit of the adaptor protein AP2 (AP2M1), a core component of the clathrin-mediated endocytic machinery. Analysis of human SH-SY5Y cells and mouse neurons and tissues revealed that loss of LRRK2 abundance or kinase function resulted in decreased phosphorylation of AP2M1, which is required for the initial formation of clathrin-coated vesicles (CCVs). In contrast, overexpression of LRRK2 or expression of a Parkinson’s disease–associated gain-of-function mutant LRRK2 (G2019S) inhibited the uncoating of AP2M1 from CCVs at later stages and prevented new cycles of CCV formation. Thus, the abundance and activity of LRRK2 must be calibrated to ensure proper endocytosis. Dysregulated phosphorylation of AP2M1 from the brain but not thyroid tissues of LRRK2 knockout and G2019S-knockin mice suggests a tissue-specific regulatory mechanism of endocytosis. Furthermore, we found that LRRK2-dependent phosphorylation of AP2M1 mediated dopaminergic neurodegeneration in a Drosophila model of PD. Together, our findings provide a mechanistic link between LRRK2, AP2, and endocytosis in the pathogenesis of PD.

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Neuron-Astrocyte Interactions in Parkinson’s Disease

Cells ◽

10.3390/cells9122623 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2623

Author(s):

Ikuko Miyazaki ◽

Masato Asanuma

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Therapeutic Strategies ◽

Pathogenic Role ◽

Waste Products ◽

Disease Modifying Drugs ◽

Dopaminergic Neurodegeneration ◽

The Central Nervous System

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

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α-Bisabolol, a Dietary Bioactive Phytochemical Attenuates Dopaminergic Neurodegeneration through Modulation of Oxidative Stress, Neuroinflammation and Apoptosis in Rotenone-Induced Rat Model of Parkinson’s Disease

Biomolecules ◽

10.3390/biom10101421 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1421 ◽

Cited By ~ 1

Author(s):

Hayate Javed ◽

M. F. Nagoor Meeran ◽

Sheikh Azimullah ◽

Lujain Bader Eddin ◽

Vivek Dhar Dwivedi ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Proinflammatory Cytokines ◽

Rat Model ◽

Inflammatory Mediators ◽

Dopaminergic Neurons ◽

Neuroprotective Effects ◽

Dopaminergic Neurodegeneration

Rotenone (ROT), a plant-derived pesticide is a well-known environmental neurotoxin associated with causation of Parkinson’s disease (PD). ROT impairs mitochondrial dysfunction being mitochondrial complex-I (MC-1) inhibitor and perturbs antioxidant-oxidant balance that contributes to the onset and development of neuroinflammation and neurodegeneration in PD. Due to the scarcity of agents to prevent the disease or to cure or halt the progression of symptoms of PD, the focus is on exploring agents from naturally occurring dietary phytochemicals. Among numerous phytochemicals, α-Bisabolol (BSB), natural monocyclic sesquiterpene alcohol found in many ornamental flowers and edible plants garnered attention due to its potent pharmacological properties and therapeutic potential. Therefore, the present study investigated the neuroprotective effects of BSB in a rat model of ROT-induced dopaminergic neurodegeneration, a pathogenic feature of PD and underlying mechanism targeting oxidative stress, inflammation and apoptosis. BSB treatment significantly prevented ROT-induced loss of dopaminergic neurons and fibers in the substantia nigra and striatum respectively. BSB treatment also attenuated ROT-induced oxidative stress evidenced by inhibition of MDA formation and GSH depletion as well as improvement in antioxidant enzymes, SOD and catalase. BSB treatment also attenuated ROT-induced activation of the glial cells as well as the induction and release of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and inflammatory mediators (iNOS and COX-2) in the striatum. In addition to countering oxidative stress and inflammation, BSB also attenuated apoptosis of dopaminergic neurons by attenuating downregulation of anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic proteins Bax, cleaved caspases-3 and 9. Further, BSB was observed to attenuate mitochondrial dysfunction by inhibiting mitochondrial lipid peroxidation, cytochrome-C release and reinstates the levels/activity of ATP and MC-I. The findings of the study demonstrate that BSB treatment salvaged dopaminergic neurons, attenuated microglia and astrocyte activation, induction of inflammatory mediators, proinflammatory cytokines and reduced the expression of pro-apoptotic markers. The in vitro study on ABTS radical revealed the antioxidant potential of BSB. The results of the present study are clearly suggestive of the neuroprotective effects of BSB through antioxidant, anti-inflammatory and anti-apoptotic properties in ROT-induced model of PD.

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