A novel super-resolution microscopy platform for cutaneous alpha-synuclein detection in Parkinson’s disease

Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD patholog...

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Published in:	Frontiers in molecular neuroscience Vol. 17; p. 1431549
Main Authors:	Sade, Ofir, Fischel, Daphna, Barak-Broner, Noa, Halevi, Shir, Gottfried, Irit, Bar-On, Dana, Sachs, Stefan, Mirelman, Anat, Thaler, Avner, Gour, Aviv, Kestenbaum, Meir, Gana Weisz, Mali, Anis, Saar, Soto, Claudio, Roitman, Melanie Shanie, Shahar, Shimon, Doppler, Kathrin, Sauer, Markus, Giladi, Nir, Lev, Nirit, Alcalay, Roy N., Hassin-Baer, Sharon, Ashery, Uri
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 04.09.2024
Subjects:	alpha-synuclein aggregates biomarker density-based spatial clustering of applications with noise (DBSCAN) direct stochastic optical reconstruction microscopy (dSTORM) early diagnosis fast optimized cluster algorithm for localizations (FOCAL) Molecular Neuroscience early diagnosis alpha-synuclein aggregates density-based spatial clustering of applications with noise (DBSCAN) direct stochastic optical reconstruction microscopy (dSTORM) biomarker Parkinson’s disease super-resolution microscopy fast optimized cluster algorithm for localizations (FOCAL)
ISSN:	1662-5099, 1662-5099
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Abstract	Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy ( d STORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto d STORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm 2 . Our d STORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status.
AbstractList	Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson's disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy ( STORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto STORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001-0.1 molecules/nm . Our STORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status. Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy ( d STORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto d STORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm 2 . Our d STORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status. Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001–0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status. Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson's disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001-0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status.Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson's disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001-0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status.
Author	Sauer, Markus Sade, Ofir Halevi, Shir Shahar, Shimon Gour, Aviv Gana Weisz, Mali Thaler, Avner Ashery, Uri Fischel, Daphna Bar-On, Dana Mirelman, Anat Roitman, Melanie Shanie Lev, Nirit Kestenbaum, Meir Giladi, Nir Hassin-Baer, Sharon Gottfried, Irit Alcalay, Roy N. Doppler, Kathrin Sachs, Stefan Soto, Claudio Barak-Broner, Noa Anis, Saar
AuthorAffiliation	3 Department of Biotechnology and Biophysics, Biocenter, University of Würzburg , Würzburg , Germany 9 Department of Statistics, Exact Sciences Faculty, Tel Aviv University , Tel Aviv , Israel 6 Department of Neurology, Meir Medical Center , Kfar Saba , Israel 8 Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, University of Texas Medical School , Houston, TX , United States 1 School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University , Tel Aviv , Israel 4 Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center , Tel Aviv , Israel 5 Faculty of Medical and Health Sciences, Tel Aviv University , Tel Aviv , Israel 7 Department of Neurology, Movement Disorders Institute, Chaim Sheba Medical Center , Ramat Gan , Israel 2 Sagol School of Neuroscience, Tel Aviv University , Tel Aviv , Israel 10 Department of Neurology, University Hospital Würzburg , Würzburg , Germany
AuthorAffiliation_xml	– name: 8 Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, University of Texas Medical School , Houston, TX , United States – name: 4 Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center , Tel Aviv , Israel – name: 7 Department of Neurology, Movement Disorders Institute, Chaim Sheba Medical Center , Ramat Gan , Israel – name: 3 Department of Biotechnology and Biophysics, Biocenter, University of Würzburg , Würzburg , Germany – name: 10 Department of Neurology, University Hospital Würzburg , Würzburg , Germany – name: 6 Department of Neurology, Meir Medical Center , Kfar Saba , Israel – name: 5 Faculty of Medical and Health Sciences, Tel Aviv University , Tel Aviv , Israel – name: 2 Sagol School of Neuroscience, Tel Aviv University , Tel Aviv , Israel – name: 9 Department of Statistics, Exact Sciences Faculty, Tel Aviv University , Tel Aviv , Israel – name: 1 School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University , Tel Aviv , Israel
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Copyright	Copyright © 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery. Copyright © 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery. 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery
Copyright_xml	– notice: Copyright © 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery. – notice: Copyright © 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery. 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery
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Keywords	early diagnosis alpha-synuclein aggregates density-based spatial clustering of applications with noise (DBSCAN) direct stochastic optical reconstruction microscopy (dSTORM) biomarker Parkinson’s disease super-resolution microscopy fast optimized cluster algorithm for localizations (FOCAL)
Language	English
License	Copyright © 2024 Sade, Fischel, Barak-Broner, Halevi, Gottfried, Bar-On, Sachs, Mirelman, Thaler, Gour, Kestenbaum, Gana Weisz, Anis, Soto, Roitman, Shahar, Doppler, Sauer, Giladi, Lev, Alcalay, Hassin-Baer, and Ashery. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Snippet	Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson’s disease (PD). ASyn aggregates have also been... Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson's disease (PD). ASyn aggregates have also been...
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SubjectTerms	alpha-synuclein aggregates biomarker density-based spatial clustering of applications with noise (DBSCAN) direct stochastic optical reconstruction microscopy (dSTORM) early diagnosis fast optimized cluster algorithm for localizations (FOCAL) Molecular Neuroscience
Title	A novel super-resolution microscopy platform for cutaneous alpha-synuclein detection in Parkinson’s disease
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