Targeting TREM2 for Parkinson’s Disease: Where to Go?

Parkinson’s disease (PD) is one of most common neurodegenerative disorders caused by a combination of environmental and genetic risk factors. Currently, numerous population genetic studies have shown that polymorphisms in myeloid cell-triggered receptor II (TREM2) are associated with a variety of neurodegenerative disorders. Recently, TREM2 has been verified to represent a promising candidate gene for PD susceptibility and progression. For example, the expression of TREM2 was apparently increased in the prefrontal cortex of PD patients. Moreover, the rare missense mutations in TREM2 (rs75932628, p.R47H) was confirmed to be a risk factor of PD. In addition, overexpression of TREM2 reduced dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of PD. Due to the complex pathogenesis of PD, there is still no effective drug treatment. Thus, TREM2 has received increasing widespread attention as a potential therapeutic target. This review focused on the variation of TREM2 in PD and roles of TREM2 in PD pathogenesis, such as excessive-immune inflammatory response, α-Synuclein aggregation and oxidative stress, to further provide evidence for new immune-related biomarkers and therapies for PD.

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Virulence test using nematodes to prescreenNocardiaspecies capable of inducing neurodegeneration and behavioral disorders

PeerJ ◽

10.7717/peerj.3823 ◽

2017 ◽

Vol 5 ◽

pp. e3823 ◽

Cited By ~ 3

Author(s):

Claire Bernardin Souibgui ◽

Anthony Zoropogui ◽

Jeremy Voisin ◽

Sebastien Ribun ◽

Valentin Vasselon ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Behavioral Disorders ◽

Neurodegenerative Disorders ◽

Dopaminergic Neuron ◽

Neuronal Damage ◽

Lung Infection ◽

C Elegans ◽

Dopaminergic Neurodegeneration ◽

Bacterial Dissemination

BackgroundParkinson’s disease (PD) is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain—some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin.Nocardiaare Actinobacteria that can cause human diseases like nocardiosis. This illness can lead to lung infection or central nervous system (CNS) invasion in both immunocompromised and immunocompetent individuals. The main species involved in CNS areN. farcinica, N. nova,N. brasiliensisandN. cyriacigeorgica. Some studies have highlighted the ability ofN. cyriacigeorgicato induce Parkinson’s disease-like symptoms in animals. Actinobacteria are known to produce a large variety of secondary metabolites, some of which can be neurotoxic. We hypothesized that neurotoxic secondary metabolite production and the onset of PD-like symptoms in animals could be linked.MethodsHere we used a method to screen bacteria that could induce dopaminergic neurodegeneration before performing mouse experiments.ResultsThe nematodeCaenorhabditis elegansallowed us to demonstrate thatNocardiastrains belonging toN. cyriacigeorgicaandN. farcinicaspecies can induce dopaminergic neurodegeneration. Strains of interest involved with the nematodes in neurodegenerative disorders were then injected in mice. Infected mice had behavioral disorders that may be related to neuronal damage, thus confirming the ability ofNocardiastrains to induce neurodegeneration. These behavioral disorders were induced byN. cyriacigeorgicaspecies (N. cyriacigeorgicaGUH-2 andN. cyriacigeorgica44484) andN. farcinica10152.DiscussionWe conclude thatC. elegansis a good model for detectingNocardiastrains involved in neurodegeneration. This model allowed us to detect bacteria with high neurodegenerative effects and which should be studied in mice to characterize the induced behavioral disorders and bacterial dissemination.

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Tuning Hsp104 specificity to selectively detoxify α-synuclein

10.1101/2020.04.15.043935 ◽

2020 ◽

Cited By ~ 2

Author(s):

Korrie L. Mack ◽

Hanna Kim ◽

Meredith E. Jackrel ◽

JiaBei Lin ◽

Jamie E. DeNizio ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substrate Specificity ◽

Neurodegenerative Disease ◽

Neurodegenerative Disorders ◽

C Elegans ◽

Dopaminergic Neurodegeneration ◽

Aaa Protein ◽

Target Effects

SummaryHsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson’s disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

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Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer's and Parkinson's disease

Frontiers in Bioscience ◽

10.2741/2695 ◽

2008 ◽

Vol 13 (13) ◽

pp. 492 ◽

Cited By ~ 145

Author(s):

Marina, R. Picciotto

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorders

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Faculty Opinions recommendation of PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5602957.5690055 ◽

2010 ◽

Author(s):

Monte Gates ◽

Rowan Orme

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Intervention ◽

Therapeutic Target ◽

Potential Therapeutic Target

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Targeting the Nicotinic Acetylcholine Receptors (nAChRs) in Astrocytes as a Potential Therapeutic Target in Parkinson's Disease

Current Pharmaceutical Design ◽

10.2174/138161282210160304112133 ◽

2016 ◽

Vol 22 (10) ◽

pp. 1305-1311 ◽

Cited By ~ 24

Author(s):

Juan Camilo Jurado-Coronel ◽

Marco Avila-Rodriguez ◽

Francisco Capani ◽

Janneth Gonzalez ◽

Valentina Echeverria Moran ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nicotinic Acetylcholine Receptors ◽

Therapeutic Target ◽

Acetylcholine Receptors ◽

Potential Therapeutic Target ◽

Nicotinic Acetylcholine

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Imaging Familial and Sporadic Neurodegenerative Disorders Associated with Parkinsonism

Neurotherapeutics ◽

10.1007/s13311-020-00994-4 ◽

2021 ◽

Author(s):

David J. Brooks

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorders ◽

Lewy Body Dementia ◽

Imaging Biomarkers ◽

Imaging Findings ◽

Subclinical Disease ◽

Similarities And Differences ◽

Potential Use

AbstractIn this paper, the structural and functional imaging changes associated with sporadic and genetic Parkinson’s disease and atypical Parkinsonian variants are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed, and the potential use and drawbacks of using imaging biomarkers for monitoring disease progression is debated. Imaging changes associated with nonmotor complications of PD are presented. The similarities and differences in imaging findings in Lewy body dementia, Parkinson’s disease dementia, and Alzheimer’s disease are discussed.

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Unraveling Pathophysiological Mechanisms of Parkinson’s Disease: Contribution of CSF Biomarkers

Biomarker Insights ◽

10.1177/1177271920964077 ◽

2020 ◽

Vol 15 ◽

pp. 117727192096407

Author(s):

Lucia Farotti ◽

Federico Paolini Paoletti ◽

Simone Simoni ◽

Lucilla Parnetti

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical History ◽

Substantial Contribution ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Disease Modifying Drugs ◽

Precise Diagnosis ◽

And Oxidative Stress

Diagnosis of Parkinson’s disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer’s disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.

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