<scp>p</scp>62 Deficiency Enhances α‐Synuclein Pathology in Mice

<jats:title>Abstract</jats:title><jats:p>In <jats:styled-content style="fixed-case">L</jats:styled-content>ewy body disease (<jats:styled-content style="fixed-case">LBD</jats:styled-content>) such as dementia with <jats:styled-content style="fixed-case">LBs</jats:styled-content> and <jats:styled-content style="fixed-case">P</jats:styled-content>arkinson's disease, several lines of evidence show that disrupted proteolysis occurs. <jats:styled-content style="fixed-case">p</jats:styled-content>62/<jats:styled-content style="fixed-case">SQSTM</jats:styled-content>1 (<jats:styled-content style="fixed-case">p</jats:styled-content>62) is highly involved with intracellular proteolysis and is a component of ubiquitin‐positive inclusions in various neurodegenerative disorders. However, it is not clear whether <jats:styled-content style="fixed-case">p</jats:styled-content>62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of <jats:styled-content style="fixed-case">LBD</jats:styled-content> that lacks <jats:styled-content style="fixed-case">p</jats:styled-content>62, and found that <jats:styled-content style="fixed-case">LB</jats:styled-content>‐like inclusions were observed in transgenic mice that overexpressed α‐synuclein (<jats:styled-content style="fixed-case">T</jats:styled-content>g mice) with or without the <jats:styled-content style="fixed-case">p</jats:styled-content>62 protein. <jats:styled-content style="fixed-case">p</jats:styled-content>62 deficiency enhanced α‐synuclein pathology with regard to the number of inclusions and staining intensity compared with <jats:styled-content style="fixed-case">T</jats:styled-content>g mice that expressed <jats:styled-content style="fixed-case">p</jats:styled-content>62. To further investigate the molecular mechanisms associated with the loss of <jats:styled-content style="fixed-case">p</jats:styled-content>62 in <jats:styled-content style="fixed-case">T</jats:styled-content>g mice, we assessed the <jats:styled-content style="fixed-case"><jats:italic>mRNA</jats:italic></jats:styled-content> and protein levels of several molecules, and found that the neighbor of the brca1 gene (<jats:italic><jats:styled-content style="fixed-case">NB</jats:styled-content>r1</jats:italic>), which is functionally and structurally similar to <jats:styled-content style="fixed-case">p</jats:styled-content>62, is increased in <jats:styled-content style="fixed-case">T</jats:styled-content>g mice without <jats:styled-content style="fixed-case">p</jats:styled-content>62 compared with control <jats:styled-content style="fixed-case">T</jats:styled-content>g mice. These findings suggest that <jats:styled-content style="fixed-case">p</jats:styled-content>62 and <jats:styled-content style="fixed-case">NBR</jats:styled-content>1 affect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α‐synuclein aggregation.</jats:p>