Nigral Neurons Degenerating in Parkinson&apos;s Disease Express the Angiotensin Receptor Type 1 Gene

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Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease

Tushar Kamath, Abdulraouf Abdulraouf, S. Burris … (2022)

The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.

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Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death

Ana I. Rodriguez-Perez, Diego Sucunza, Maria A. Pedrosa … (2018)

The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson’s disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD. Electronic supplementary material The online version of this article (10.1007/s13311-018-0646-z) contains supplementary material, which is available to authorized users.

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Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

Youngkwon Jo, Seungyeon Kim, Byoung Seok Ye … (2022)

Background: Renin-angiotensin system (RAS) inhibitors have been suggested as protective agents in Parkinson’s disease (PD). However, epidemiological evidence on the association between RAS inhibitors and the development of PD is inconsistent. Objectives: To investigate the effect of RAS inhibitors on PD risk in patients with ischemic heart disease (IHD) by type and cumulative duration of RAS inhibitors and their degree of blood-brain barrier (BBB) penetration ability. Methods: This was a propensity score-matched retrospective cohort study using 2008–2019 healthcare claims data from the Korean Health Insurance Review and Assessment database. The association between RAS inhibitor use and PD in patients with IHD was evaluated using multivariate Cox proportional hazard regression analysis. The risks are presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: Over a 10-year follow-up, 1,086 of 62,228 IHD patients developed PD. The Cox regression model showed that the use of RAS inhibitors was significantly associated with a lower risk of PD (aHR = 0.75; 95% CI 0.66–0.85) than the non-use of RAS inhibitors. Specifically, this reduced risk of PD only remained with the use of BBB-crossing angiotensin II receptor blockers (ARBs) (aHR = 0.62; 95% CI = 0.53–0.74), and this association was more definite with an increasing cumulative duration. A significantly reduced risk of PD was not observed with the use of BBB-crossing angiotensin-converting enzyme inhibitors. Conclusions: The use of ARBs with BBB-penetrating properties and a high cumulative duration significantly reduces the risk of PD in IHD patients. This protective effect could provide insight into disease-modifying drug candidates for PD.

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Contributors

Jose L. Labandeira‐Garcia:

ORCID: https://orcid.org/0000-0002-8243-9791

joseluis.labandeira@usc.es

Journal

Journal ID (nlm-ta): Mov Disord

Journal ID (iso-abbrev): Mov Disord

Journal ID (doi): 10.1002/(ISSN)1531-8257

Journal ID (publisher-id): MDS

Title: Movement Disorders

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 0885-3185

ISSN (Electronic): 1531-8257

Publication date (Electronic): 29 June 2022

Publication date (Print): August 2022

Volume: 37

Issue: 8 ( doiID: 10.1002/mds.v37.8 )

Pages: 1610-1611

Affiliations

[ ¹ ] Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS University of Santiago de Compostela Santiago de Compostela Spain

Author notes

[*] [* ] Correspondence to: Prof. Jose L. Labandeira‐Garcia, Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain; E‐mail: joseluis.labandeira@ 123456usc.es

Author information

Jose L. Labandeira‐Garcia https://orcid.org/0000-0002-8243-9791

Juan A. Parga https://orcid.org/0000-0003-2072-5642

Article

Publisher ID: MDS29137

DOI: 10.1002/mds.29137

PMC ID: 9544027

PubMed ID: 35766438

SO-VID: c83826d5-c44f-455a-b11c-8f822a741299

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This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 01 June 2022

Date received : 25 May 2022

Date accepted : 06 June 2022

Page count

Figures: 1, Tables: 0, Pages: 2, Words: 766

Funding

Funded by: Secretaría de Estado de Investigación, Desarrollo e Innovación , doi 10.13039/501100007136;

Award ID: RTI2018‐098830‐B‐100

Custom metadata

source-schema-version-number 2.0

cover-date August 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.0 mode:remove_FC converted:07.10.2022

Nigral Neurons Degenerating in Parkinson's Disease Express the Angiotensin Receptor Type 1 Gene

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Most cited references 5

Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease

Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death

Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

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