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Quantitative Characterization of α-Synuclein Aggregation in Living Cells through Automated Microfluidics Feedback Control

Perrino, Giansimone; Wilson, Cathal; Santorelli, Marco; di Bernardo, Diego


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    <dct:title>Quantitative Characterization of α-Synuclein Aggregation in Living Cells through Automated Microfluidics Feedback Control</dct:title>
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    <dcat:keyword>Bioengineering</dcat:keyword>
    <dcat:keyword>Microfluidics</dcat:keyword>
    <dcat:keyword>Feedback control</dcat:keyword>
    <dcat:keyword>Gene expression</dcat:keyword>
    <dcat:keyword>Synuclein</dcat:keyword>
    <dcat:keyword>Aggregation</dcat:keyword>
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    <dct:description>&lt;p&gt;&lt;strong&gt;Highlights&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;&amp;bull;&amp;nbsp;&lt;em&gt;In silico&lt;/em&gt;&amp;nbsp;feedback control enables regulation of &amp;alpha;-synuclein expression in yeast&lt;/p&gt; &lt;p&gt;&amp;bull;&amp;nbsp;&amp;alpha;-Synuclein inclusion formation is strictly concentration, but not time, dependent&lt;/p&gt; &lt;p&gt;&amp;bull;&amp;nbsp;The aggregation threshold of the &amp;alpha;-synuclein A53T mutant is 56% of the wild-type&lt;/p&gt; &lt;p&gt;&amp;bull;&amp;nbsp;Autophagy induction speeds up inclusion clearance in the A53T &amp;alpha;-synuclein strain&lt;/p&gt; &lt;p&gt;&lt;strong&gt;Summary&lt;/strong&gt;&lt;/p&gt; &lt;p&gt;Aggregation of&amp;nbsp;&amp;alpha;-synuclein&amp;nbsp;and formation of inclusions are hallmarks of Parkinson&amp;rsquo;s disease (PD). Aggregate formation is affected by cellular environment, but it has been studied almost exclusively in cell-free systems. We quantitatively analyzed &amp;alpha;-synuclein inclusion formation and clearance in a yeast cell model of PD expressing either&amp;nbsp;wild-type&amp;nbsp;(WT) &amp;alpha;-synuclein or the disease-associated A53T mutant from the&amp;nbsp;galactose&amp;nbsp;(Gal)-inducible promoter. A computer-controlled microfluidics device regulated &amp;alpha;-synuclein in cells by means of closed-loop feedback control. We demonstrated that inclusion formation is strictly concentration dependent and that the aggregation threshold of the A53T mutant is about half of the WT &amp;alpha;-synuclein (56%). We chemically modulated the proteasomal&amp;nbsp;and autophagic pathways and demonstrated that&amp;nbsp;autophagy&amp;nbsp;is the main determinant of A53T &amp;alpha;-synuclein inclusions&amp;rsquo; clearance. In addition to proposing a technology to overcome current limitations in dynamically regulating&amp;nbsp;protein expression&amp;nbsp;levels, our results contribute to the&amp;nbsp;biology&amp;nbsp;of PD and have relevance for therapeutic applications.&lt;/p&gt;</dct:description>
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