CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation

The pathological accumulation of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Synuclein (<inline-fo...

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Autores principales:	Lea Elsholz, Yasmine Wasser, Patrick Ziegler, Pardes Habib, Aaron Voigt
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CK1BP CK1 α-Synuclein α-Synuclein oligomerization α-Synuclein aggregation Parkinson’s disease Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4167b442f4db4701b03eff41f93c238e
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id	oai:doaj.org-article:4167b442f4db4701b03eff41f93c238e
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	CK1BP CK1 α-Synuclein α-Synuclein oligomerization α-Synuclein aggregation Parkinson’s disease Biology (General) QH301-705.5
spellingShingle	CK1BP CK1 α-Synuclein α-Synuclein oligomerization α-Synuclein aggregation Parkinson’s disease Biology (General) QH301-705.5 Lea Elsholz Yasmine Wasser Patrick Ziegler Pardes Habib Aaron Voigt CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
description	The pathological accumulation of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Synuclein (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn) is the hallmark of neurodegenerative <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-synucleinopathies, including Parkinsons’s disease (PD). In contrast to the mostly non-phosphorylated soluble <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn, aggregated <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn is usually phosphorylated at serine 129 (S129). Therefore, S129-phosphorylation is suspected to interfere with <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn aggregation. Among other kinases, protein kinase CK1 (CK1) is known to phosphorylate <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn at S129. We overexpressed CK1 binding protein (CK1BP) to inhibit CK1 kinase activity. Using Bimolecular Fluorescence Complementation (BiFC) in combination with biochemical methods, we monitored the S129 phosphorylation and oligomerization of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn in HEK293T cells. We found that CK1BP reduced the overall protein levels of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn. Moreover, CK1BP concomitantly reduced S129 phosphorylation, oligomerization and the amount of insoluble <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn. Analyzing different <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn variants including S129 mutations, we show that the effects of CK1BP on <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn accumulation were independent of S129 phosphorylation. Further analysis of an aggregating polyglutamine (polyQ) protein confirmed a phosphorylation-independent decrease in aggregation. Our results imply that the inhibition of CK1 activity by CK1BP might exert beneficial effects on NDDs in general. Accordingly, CK1BP represents a promising target for the rational design of therapeutic approaches to cease or at least delay the progression of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-synucleinopathies.
format	article
author	Lea Elsholz Yasmine Wasser Patrick Ziegler Pardes Habib Aaron Voigt
author_facet	Lea Elsholz Yasmine Wasser Patrick Ziegler Pardes Habib Aaron Voigt
author_sort	Lea Elsholz
title	CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
title_short	CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
title_full	CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
title_fullStr	CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
title_full_unstemmed	CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation
title_sort	ck1bp reduces α-synuclein oligomerization and aggregation independent of serine 129 phosphorylation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4167b442f4db4701b03eff41f93c238e
work_keys_str_mv	AT leaelsholz ck1bpreducesasynucleinoligomerizationandaggregationindependentofserine129phosphorylation AT yasminewasser ck1bpreducesasynucleinoligomerizationandaggregationindependentofserine129phosphorylation AT patrickziegler ck1bpreducesasynucleinoligomerizationandaggregationindependentofserine129phosphorylation AT pardeshabib ck1bpreducesasynucleinoligomerizationandaggregationindependentofserine129phosphorylation AT aaronvoigt ck1bpreducesasynucleinoligomerizationandaggregationindependentofserine129phosphorylation
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spelling	oai:doaj.org-article:4167b442f4db4701b03eff41f93c238e2021-11-25T17:07:41ZCK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation10.3390/cells101128302073-4409https://doaj.org/article/4167b442f4db4701b03eff41f93c238e2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2830https://doaj.org/toc/2073-4409The pathological accumulation of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Synuclein (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn) is the hallmark of neurodegenerative <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-synucleinopathies, including Parkinsons’s disease (PD). In contrast to the mostly non-phosphorylated soluble <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn, aggregated <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn is usually phosphorylated at serine 129 (S129). Therefore, S129-phosphorylation is suspected to interfere with <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn aggregation. Among other kinases, protein kinase CK1 (CK1) is known to phosphorylate <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn at S129. We overexpressed CK1 binding protein (CK1BP) to inhibit CK1 kinase activity. Using Bimolecular Fluorescence Complementation (BiFC) in combination with biochemical methods, we monitored the S129 phosphorylation and oligomerization of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn in HEK293T cells. We found that CK1BP reduced the overall protein levels of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn. Moreover, CK1BP concomitantly reduced S129 phosphorylation, oligomerization and the amount of insoluble <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn. Analyzing different <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn variants including S129 mutations, we show that the effects of CK1BP on <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-Syn accumulation were independent of S129 phosphorylation. Further analysis of an aggregating polyglutamine (polyQ) protein confirmed a phosphorylation-independent decrease in aggregation. Our results imply that the inhibition of CK1 activity by CK1BP might exert beneficial effects on NDDs in general. Accordingly, CK1BP represents a promising target for the rational design of therapeutic approaches to cease or at least delay the progression of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">α</mi></semantics></math></inline-formula>-synucleinopathies.Lea ElsholzYasmine WasserPatrick ZieglerPardes HabibAaron VoigtMDPI AGarticleCK1BPCK1α-Synucleinα-Synuclein oligomerizationα-Synuclein aggregationParkinson’s diseaseBiology (General)QH301-705.5ENCells, Vol 10, Iss 2830, p 2830 (2021)

CK1BP Reduces α-Synuclein Oligomerization and Aggregation Independent of Serine 129 Phosphorylation

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