Alpha-synuclein as therapeutic target in Parkinson’s disease

Franziska Richter Assêncio

doi:10.1515/nf-2018-0029

Article

Alpha-synuclein as therapeutic target in Parkinson’s disease

Franziska Richter graduated 2007 in Veterinary Medicine (Dr. med. vet.) at the FU Berlin working on animal models of Parkinson´s disease. As a postdoc and research faculty in the lab of Marie-Francoise Chesselet, Department of Neurology at UCLA (2007–2012), she performed several preclinical trials in mouse models of alpha-synuclein pathology. In 2012 she joined Prof. Angelika Richter at the Faculty of Veterinary Medicine in Leipzig, extending her field to therapeutic interventions in dystonia. She is currently Professor and Chair of the Department of Pharmacology, Toxicology and Pharmacy at the University of Veterinary Medicine Hannover.

Published/Copyright: June 4, 2019

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From the journal Neuroforum Volume 25 Issue 2

Zusammenfassung

180 Jahre vergingen zwischen James Parkinson’s “An essay on the shaking palsy” und der Entdeckung der zentralen Rolle von alpha-synuclein in der Pathogenese von Parkinson’s disease (PD). Der Identifikation einer PD verursachenden Mutation im alpha-synuclein Gen folgte rasch der Nachweis des Proteins in Lewy Körperchen, den charakteristischen Proteineinschlüssen im Gehirn der Patienten. Trotz vieler ungeklärter Fragen, Forschungsergebnisse zur Entstehung, Ausbreitung und Neurotoxizität der alpha-synuclein Pathologie geben Hoffnung auf die Entwicklung einer Krankheits-modifizierenden Therapie, über die Dopaminersatztherapie hinaus. Die Hypothese, dass alpha-synuclein Pathologie sich ähnlich wie ein Prion ausbreitet, wird kontrovers diskutiert, und initiierte viele interessante neue Forschungsansätze und therapeutische Zielstrukturen. Dieser Übersichtsartikel fasst die Evidenz für eine zentrale Rolle von alpha-synuclein in der Pathogenese der PD zusammen, gefolgt von einer Diskussion neuer Therapiestrategien.

Abstract

It took 180 years from James Parkinson’s descriptions in “An essay on the shaking palsy” to the discovery of alpha-synuclein as key player in Parkinson’s disease (PD). The identification of a PD causing mutation in the gene of alpha-synuclein was followed immediately by detection of its presence in Lewy bodies, inclusions found in the brains of patients. While many open questions remain, findings on how alpha-synuclein pathology emerges, propagates and causes neuronal death provide hope for development of disease-modifying therapeutics beyond the current dopamine replacement therapy. The recent hypothesis of a prion-like transmission of alpha-synuclein pathology raises controversy but also inspired numerous exciting research avenues, partially already translating into novel drug targets. This review summarizes evidence for a critical role of alpha-synuclein in PD pathogenesis followed by a discussion of current promising treatment avenues.

Keywords: synucleinopathy; prion; neurodegeneration; neuroprotection; dopamine

About the author

Prof. Dr. Franziska Richter Assêncio

Franziska Richter graduated 2007 in Veterinary Medicine (Dr. med. vet.) at the FU Berlin working on animal models of Parkinson´s disease. As a postdoc and research faculty in the lab of Marie-Francoise Chesselet, Department of Neurology at UCLA (2007–2012), she performed several preclinical trials in mouse models of alpha-synuclein pathology. In 2012 she joined Prof. Angelika Richter at the Faculty of Veterinary Medicine in Leipzig, extending her field to therapeutic interventions in dystonia. She is currently Professor and Chair of the Department of Pharmacology, Toxicology and Pharmacy at the University of Veterinary Medicine Hannover.

Acknowledgments

The author is grateful to Marie-Francoise Chesselet and members of her lab for a great and inspiring time at UCLA, resulting in work cited in this review, funded by NIH, MJFF, APDA and a fellowship of the Alexander von Humboldt foundation. In Leipzig, the author would like to thank Angelika Richter and Achim Aigner for collaboration and support on studies of nanoparticle mediated alpha-synuclein delivery.

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Response to Reviewers

I am grateful to both reviewers for the excellent suggestions and corrections. Please find below my response to each point.

Reviewer: 1

Comments to the Author

Richter et al in the manuscript titled “Alpha-synuclein as therapeutic target in Parkinson’s disease” provide a review on disease-modifying treatment approaches in development in PD targeting specifically alpha-synuclein.

1. In the abstract the authors refer to prion-like hypothesis in PD in relation to alpha-synuclein transmission from enteric nervous system to CNS. However, prion-like hypothesis and the role of prion-like mechanism in PD is not restricted to above mentioned plausible mode of transmission, therefore I would suggest that authors rephrase this sentence.

The sentence has been shortened: “The recent hypothesis of a prion-like transmission of alpha-synuclein pathology raises controversy but also inspired numerous exciting research avenues.”

2. Neurodegeneration in PD is not at all restricted to dopaminergic neurones in the substantia nigra (i. e. it is not correct to stay it predominantly involves dopamine neurones – the main symptoms are due to loss of these neurones in the substantia nigra, but there are many other neurones in the brain affected (leading to a myriad of additional clinical symptoms). Therefore, I suggest to rephrase this sentence.

The sentence has been rephrased: “Neurodegeneration in PD affects diverse neuronal subtypes, including dopamine neurons of the substantia nigra pars compacta.”

3. In Dementia with Lewy bodies (DLB) alpha-synuclein pathology accumulates not only in cortical areas. In fact, on histological grounds advanced PD and DLB is indistinguishable and also on clinical grounds the main distinguishing feature is based on arbitrary defined onset of cognitive impairment. Therefore, I strongly recommend that this paragraph is rephrased (lines 55–57, page 4).

This paragraph has been modified: “Lewy bodies are also found in neurocognitive disorders such as Dementia with Lewy bodies (DLB). DLB is commonly distinguished from Parkinson’s disease dementia (PDD) based on arbitrary defined earlier onset of cognitive impairment compared to motor symptoms. Both PD and DLB overlap in many clinical features, genetics, neuropathology, and management and are therefore currently regarded as subtypes of an alpha-synuclein-associated disease spectrum.”

4. In the discussion of enteric nervous system involvement in PD I would suggest that the following papers are also discussed: PMID: 29422109; PMID: 29039141.

The following discussion was added: Interestingly, while inoculation of nigral Lewy body-enriched fractions from postmortem PD brains in mice promoted alpha-synuclein pathology and dopaminergic neurodegeneration (Recasens et al., 2014), the same approach using alpha-synuclein-containing Lewy body extracts purified from peripheral postmortem stellate ganglia did not trigger respective pathology (Recasens et al., 2018). For a definite answer on how alpha-synuclein pathology propagates, further research is required to dissect mechanisms underlying the different pathogenic capacity observed in the aforementioned studies, also including alpha-synuclein aggregates from other peripheral regions, and at different disease stages. (…) Furthermore, development of specific PET-imaging tracers to track different forms of pathological alpha-synuclein in the periphery and CNS in patients could greatly advance the field (Lionnet et al., 2018).

5. I suggest to change “striata” to dorsal striatum, or specify exact nuclei (i. e. caudate nucleus and putamen) where mesenchephalic neurones had been transplanted in the cited study.

Striata was replaced with putamen and caudate nucleus.

6. In the paragraph discussing the therapeutic approaches aimed at reducing expression of alpha-synuclein, it would be important and timely to discuss the role of antisense oligonucleotides in PD treatment (PMID: 29273501).

The following sentence has been added: “Similarly, antisense oligonucleotides (ASO) against alpha-synuclein mRNA and conjugated with a monoamine uptake inhibitor achieved protein knock-down in brainstem of mice up to three days after 4 consecutive days of intranasal application (Alarcon-Aris et al., 2018).”

7. In the lines 43–44, page 9: “ … with difficult to predict effects and side effects …” This extract does not read well, I suggest to rephrase.

This has been rephrased: “Still, cumulative effects and side effects are difficult to predict.”

8. In terms of challenges measuring alpha-synuclein in clinical trials, I think it would be valuable to discuss briefly the current advances in the measuring alpha-synuclein in CSF (e. g. PMID: 27752516).

We have added a recent citation that reviews this topic: Of note, novel sensitive protein assays for detection of misfolded alpha-synuclein in cerebrospinal fluid of patients have the potential to be effective tools for the early diagnosis of synucleinopathies (Paciotti et al., 2018).

Reviewer: 2

Comments to the Author

Dieser Review beschreibt die Geschichte der Parkinson Erkrankung, die zentrale Rolle von Synuclein und der Lewy Körper, die zentrale Rolle der Entdeckung von Prof. Heiko Braak und zieht schließlich therapeutische Konsequenzen, die in die Zukunft zeigen.

Die Arbeit ist völlig überzeugend; ich habe nur einige Verbesserungsvorschläge:

1. Ich glaube, dass es nicht ganz richtig ist, allein das Paper von Ehringer und Hornykiewicz zu zitieren; ich würde dazu raten auch die Ergebnisse aus Göteborg in der Reserpin depletierten Ratte zu zitieren; immerhin hat es dafür den Nobelpreis gegeben.

Der folgende Satz wurde hinzugefügt: Arvid Carlsson, using the vesicular monoamine transporter inhibitor reserpine in rodents and rabbits, identified a major role of dopamine in brain and the potential of its precursor 3,4-dihydroxyphenylalanine (DOPA) to counteract the “tranquillizing” effects of reserpine in vivo (Carlsson et al., 1957; Carlsson et al., 1958).

2. Man könnte die Diskussion um die vagotomierten Patienten etwas ausgeglichener gestalten; immerhin sind es zwei große Studien, die – natürlich nicht beweisende – Hinweise geben; man sollte auch die positiven Hinweise zitieren und mit einem relativierenden Satz aus der Arbeit von Ole Tysnes und Mitarbeitern schließen.

Der Satz wurde modifiziert: “Truncal vagotomy was reported to reduce the risk to develop PD (Svensson et al., 2015; Liu et al., 2017), but others did not arrive at the same conclusion (Tysnes et al., 2015).”

3. Ich glaube dass die Rolle von Heiko Braak richtig dargestellt wird. Er würde aber nie sein Konzept als „prion concept“ bezeichnen; er würde immer vorsichtig „prion – like“ sagen. Ich würde dies ändern. Außerdem könnte man noch etwas präzisieren; sein Verdienst besteht darin, dass er erkannte, dass sich die Erkrankung stereotyp, nach anatomischen Regeln, im Gehirn ausbreitet und auf diese Art und Weise konnte er aus cross-sektionalen Studien ein Stadienprinzip entwickeln, dass sich ja heute klar in der Klinik belegen lässt.

Prion wurde in prion-like geändert, und hinzugefügt: “By analyzing brains of subjects with clinical diagnosis of PD and nigral Lewy body pathology versus subjects without reference to PD symptoms but Lewy body pathology versus subjects with neither PD symptoms nor Lewy body pathology they were able to conceive a staging procedure based upon the readily recognizable topographical extent of the lesions.”

4. (Dies führt vielleicht etwas zu weit) könnte man über die Biomarker Untersuchungen beim Menschen berichten, diese zeigen ja sämtlich, dass Alpha-Synuclein extrazellulär reduziert ist. Dies weist wiederum daraufhin, dass die Toxizität intrazellulär ist oder eine andere Synuclein Spezies (mit-) verantwortlich ist.

Da die Datenlage dazu nach wie vor sehr heterogen ist wurde wie folgt diskutiert: “Several studies aiming to define a biomarker for PD have reported decreased extracellular alpha-synuclein levels; however, others found increased levels (Malek et al., 2014). Recently alpha-synuclein was reported in extracellular vesicles which are released from neurons and other CNS cells and may present a reservoir for biomarkers (Gamez-Valero et al., 2019).”

Published Online: 2019-06-04

Published in Print: 2019-05-27

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https://doi.org/10.1515/nf-2018-0029

Keywords for this article

synucleinopathy; prion; neurodegeneration; neuroprotection; dopamine