Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.

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Parkinson’s Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread

Cells ◽

10.3390/cells10040746 ◽

2021 ◽

Vol 10 (4) ◽

pp. 746

Author(s):

Yingzhuo Ding ◽

Yan Li ◽

Gaurav Chhetri ◽

Xiaoxin Peng ◽

Jing Wu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Ectopic Expression ◽

Lewy Bodies ◽

Cell Protein ◽

Causative Mutation ◽

Virus Spread ◽

Cell Surfaces ◽

Vacuolar Protein ◽

Hsv 1

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects. Tetherin is a host cell protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less Tetherin on cell surfaces. Real-time and static cell imaging revealed that Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders Tetherin trafficking to cell surfaces and facilitates virus spread.

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Potential Role of Caffeine in the Treatment of Parkinson’s Disease

The Open Neurology Journal ◽

10.2174/1874205x01610010042 ◽

2016 ◽

Vol 10 (1) ◽

pp. 42-58 ◽

Cited By ~ 8

Author(s):

Mohsin H.K. Roshan ◽

Amos Tambo ◽

Nikolai P. Pace

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Clinical Trials ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Muscle Rigidity ◽

Therapeutic Effects ◽

Motor Symptoms ◽

Wide Range

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from bothin vivoandin vitrostudies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2Areceptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.

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Parkinson's Disease Genetics and Pathophysiology

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-100720-034518 ◽

2021 ◽

Vol 44 (1) ◽

pp. 87-108

Author(s):

Gabriel E. Vázquez-Vélez ◽

Huda Y. Zoghbi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Variants ◽

Neurodegenerative Disorder ◽

Disease Risk ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Disease Modifying ◽

Common Neurodegenerative Disorder

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.

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Astrocytic Oxidative/Nitrosative Stress Contributes to Parkinson’s Disease Pathogenesis: The Dual Role of Reactive Astrocytes

Antioxidants ◽

10.3390/antiox8080265 ◽

2019 ◽

Vol 8 (8) ◽

pp. 265 ◽

Cited By ~ 17

Author(s):

Asha Rizor ◽

Edward Pajarillo ◽

James Johnson ◽

Michael Aschner ◽

Eunsook Lee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nitrosative Stress ◽

Critical Role ◽

Substantia Nigra Pars Compacta ◽

Environmental Toxicants ◽

Oxidative And Nitrosative Stress ◽

Reactive Astrogliosis ◽

The Impact

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide; it is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta, but its etiology is not fully understood. Astrocytes, a class of glial cells in the central nervous system (CNS), provide critical structural and metabolic support to neurons, but growing evidence reveals that astrocytic oxidative and nitrosative stress contributes to PD pathogenesis. As astrocytes play a critical role in the production of antioxidants and the detoxification of reactive oxygen and nitrogen species (ROS/RNS), astrocytic oxidative/nitrosative stress has emerged as a critical mediator of the etiology of PD. Cellular stress and inflammation induce reactive astrogliosis, which initiates the production of astrocytic ROS/RNS and may lead to oxidative/nitrosative stress and PD pathogenesis. Although the cause of aberrant reactive astrogliosis is unknown, gene mutations and environmental toxicants may also contribute to astrocytic oxidative/nitrosative stress. In this review, we briefly discuss the physiological functions of astrocytes and the role of astrocytic oxidative/nitrosative stress in PD pathogenesis. Additionally, we examine the impact of PD-related genes such as α-synuclein, protein deglycase DJ-1( DJ-1), Parkin, and PTEN-induced kinase 1 (PINK1) on astrocytic function, and highlight the impact of environmental toxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, manganese, and paraquat, on astrocytic oxidative/nitrosative stress in experimental models.

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Chaperone-Mediated Autophagy and Mitochondrial Homeostasis in Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2016/2613401 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7

Author(s):

Ruixin Yang ◽

Guodong Gao ◽

Zixu Mao ◽

Qian Yang

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Mitochondrial Homeostasis ◽

New Findings ◽

Novel Therapeutic Strategies ◽

Chaperone Mediated Autophagy

Parkinson’s disease (PD), a complex neurodegenerative disorder, is pathologically characterized by the formation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial dysfunction is considered to be one of the most important causative mechanisms. In addition, dysfunction of chaperone-mediated autophagy (CMA), one of the lysosomal proteolytic pathways, has been shown to play an important role in the pathogenesis of PD. An exciting and important development is recent finding that CMA and mitochondrial quality control may be linked. This review summarizes the studies revealing the link between autophagy and mitochondrial function. Discussions are focused on the connections between CMA and mitochondrial failure and on the role of MEF2D, a neuronal survival factor, in mediating the regulation of mitochondria in the context of CMA. These new findings highlight the need to further explore the possibility of targeting the MEF2D-mitochondria-CMA network in both understanding the PD pathogenesis and developing novel therapeutic strategies.

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LRRK2 at the Crossroad of Aging and Parkinson’s Disease

Genes ◽

10.3390/genes12040505 ◽

2021 ◽

Vol 12 (4) ◽

pp. 505

Author(s):

Eun-Mi Hur ◽

Byoung Dae Lee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Late Onset ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Cellular Functions ◽

Lewy Neurites ◽

Clinical Presentations ◽

Lrrk2 Gene ◽

Cellular Dysfunction

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far from clear, but aging has been considered as the highest risk factor influencing the clinical presentations and the progression of PD. Accumulating evidence suggests that aging and PD induce common changes in multiple cellular functions, including redox imbalance, mitochondria dysfunction, and impaired proteostasis. Age-dependent deteriorations in cellular dysfunction may predispose individuals to PD, and cellular damages caused by genetic and/or environmental risk factors of PD may be exaggerated by aging. Mutations in the LRRK2 gene cause late-onset, autosomal dominant PD and comprise the most common genetic causes of both familial and sporadic PD. LRRK2-linked PD patients show clinical and pathological features indistinguishable from idiopathic PD patients. Here, we review cellular dysfunctions shared by aging and PD-associated LRRK2 mutations and discuss how the interplay between the two might play a role in PD pathologies.

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Drosophila melanogaster a versatile model of Parkinson’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210208125912 ◽

2021 ◽

Vol 20 ◽

Author(s):

Falaq Naz ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Maintenance Cost ◽

The Novel ◽

Life Threatening ◽

Non Motor Symptoms ◽

The Brain

: Parkinson's Disease (PD) is one of the most prevalent, recurrent and life-threatening neurodegenerative disease. However, the precise mechanism underlying this disease is not yet clearly understood. For understanding the pathogenesis of PD, it is essential to identify the symptoms along with the novel biological markers and to develop strategies which could lead towards the development of effective therapy. PD is associated with Lewy bodies (LBs) formation and the loss of dopaminergic neurons in the substantia nigra pars compacta of mid brain region. For the improvement in treatment strategiesas well as understanding the pathophysiology of the PD in number ofanimal models have been introduced that can recapitulatethe pathophysiology, motor and non-motor symptoms of PD. In contrast to mammalian models like rodents, mice and monkey, Drosophila is easy to handle as well as it maintenance cost is low.Due to the anatomical differencesin the brain and other major organsof human and fly,the issues of standardizing the methods or experiments to analyze behavioral aspects (walking, writhing, eating and sleeping) are difficult in flies. Thepresent review highlights the studies carried out for PD since 2000, using Drosophila melanogaster.

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Pesticides and Parkinson’s Disease

The Scientific World JOURNAL ◽

10.1100/tsw.2001.35 ◽

2001 ◽

Vol 1 ◽

pp. 207-208 ◽

Cited By ~ 14

Author(s):

Todd B. Sherer ◽

Ranjita Betarbet ◽

J. Timothy Greenamyre

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Selective Death ◽

Underlying Mechanisms ◽

Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

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Two Types of Spheroid Bodies in the Nigral Neurons in Parkinson's Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100031838 ◽

1991 ◽

Vol 18 (3) ◽

pp. 287-294 ◽

Cited By ~ 17

Author(s):

Tatsuo Yamada ◽

Haruhiko Akiyama ◽

Patrick L. McGeer

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Staining Pattern ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Striatonigral Degeneration ◽

Neurologically Normal ◽

Normal Controls ◽

Dystrophic Dendrites

ABSTRACT:Dendritic spheroid bodies (SBs) and Lewy bodies (LBs) were identified in comparable numbers in the substantia nigra pars compacta (SBC) of nine parkinsonian cases and one case of striatonigral degeneration but were not found irt cases of Huntington's disease or neurologically normal controls. The immunohistochemical profile of the SBs in dystrophic dendrites of nigrostriatal dopaminergic neurons was remarkably similar to that of the LBs found within dendrites or free of the SNC neuropil. Both types of inclusions stained positively with antibodies to tyrosine hydroxylase, ubiquitin and microtubule-associated protein-2 (MAP2), and negatively for Tau-2, although they had different ultrastructural appearances. A few intracellular LBs were stained by antibodies to neurofilament proteins (NFs) 68, 160, and 200 kD, but dendritic SBs and extracellular LBs were not so stained. These data indicate that dendritic SBs and extracellular LBs may have a common molecular pathogenetic origin in Parkinson's disease. On the other hand, the SBs seen in the pars reticulata (SNR) and in the distal nigrostriatal axons even in control cases were generally stained by antibodies to NFs and ubiquitin but not to MAP2. This latter staining pattern in similar to that shown by SBs in the anterior horn in ALS and in the cerebellum of neurologically normal brains and is believed typical of axonal as opposed to dendritic SBs.

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When Friendship Turns Sour: Effective Communication Between Mitochondria and Intracellular Organelles in Parkinson's Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.607392 ◽

2020 ◽

Vol 8 ◽

Author(s):

Tsu-Kung Lin ◽

Kai-Jung Lin ◽

Kai-Lieh Lin ◽

Chia-Wei Liou ◽

Shang-Der Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Stress Responses ◽

Redox Homeostasis ◽

Lewy Bodies ◽

Neuronal Loss ◽

Physical Contact ◽

Substantia Nigra Pars Compacta ◽

Intracellular Organelles ◽

Pleiotropic Functions

Parkinson's disease (PD) is a complex neurodegenerative disease with pathological hallmarks including progressive neuronal loss from the substantia nigra pars compacta and α-synuclein intraneuronal inclusions, known as Lewy bodies. Although the etiology of PD remains elusive, mitochondrial damage has been established to take center stage in the pathogenesis of PD. Mitochondria are critical to cellular energy production, metabolism, homeostasis, and stress responses; the association with PD emphasizes the importance of maintenance of mitochondrial network integrity. To accomplish the pleiotropic functions, mitochondria are dynamic not only within their own network but also in orchestrated coordination with other organelles in the cellular community. Through physical contact sites, signal transduction, and vesicle transport, mitochondria and intracellular organelles achieve the goals of calcium homeostasis, redox homeostasis, protein homeostasis, autophagy, and apoptosis. Herein, we review the finely tuned interactions between mitochondria and surrounding intracellular organelles, with focus on the nucleus, endoplasmic reticulum, Golgi apparatus, peroxisomes, and lysosomes. Participants that may contribute to the pathogenic mechanisms of PD will be highlighted in this review.

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