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We also performed biochemical and biophysical characterizations of PTEN\u2010induced kinase 1 (PINK1) phosphorylation of \u03b1\u2010syn.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      DLB brains show PINK1 deficiency alongside \u03b1\u2010syn and A\u03b2 co\u2010pathology. Mirroring human DLB patients,\n                      <jats:italic>APP\/PS1::pink1\u2010\/\u2010<\/jats:italic>\n                      mice spontaneously develop Lewy pathology at endogenous \u03b1\u2010syn levels, affecting both central and peripheral nervous systems with heterogeneous phenotypes. Mechanistically, PINK1 phosphorylates \u03b1\u2010syn at Thr44, suppressing A\u03b2\u2010induced \u03b1\u2010syn aggregation. Moreover, pT44\u2010\u03b1\u2010syn levels are correlated with PINK1 expression and activity in human brains.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      PINK1 deficiency synergizes with A\u03b2 to promote Lewy pathology via loss of protective \u03b1\u2010syn phosphorylation. The\n                      <jats:italic>APP\/PS1::pink1\u2010\/\u2010<\/jats:italic>\n                      model recapitulates key DLB features without \u03b1\u2010syn overexpression, offering a valuable tool for future mechanistic and therapeutic studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>PTEN\u2010induced kinase 1 (PINK1) deficiency, either through reduced expression or impaired activity, is found in human dementia with Lewy bodies (DLB) patients with amyloid beta (A\u03b2) co\u2010pathology.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PINK1 specifically phosphorylates \u03b1\u2010synuclein at Thr44, inhibiting A\u03b2\u2010induced aggregation and preventing the development of Lewy pathology.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The\n                            <jats:italic>APP\/PS1::pink1\u2010\/\u2010<\/jats:italic>\n                            mouse model recapitulates key features of human DLB, exhibiting widespread Lewy pathology and heterogeneous phenotypes.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PINK1 alterations emerge as a novel genetic risk factor for DLB, opening new avenues for diagnosis and therapeutic intervention.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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