title: Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease.
abstract: A growing number of PSEN1 mutations have been associated with dementia with Lewy bodies and familial Alzheimer's disease with concomitant α-synuclein pathology. The objective of this study was to determine if PSEN1 plays a direct role in the development of α-synuclein pathology in these diseases. Using mass spectrometry, immunoelectron microscopy and fluorescence lifetime image microscopy based on Forster resonance energy transfer (FLIM-FRET) we identified α-synuclein as a novel interactor of PSEN1 in wild-type mouse brain tissue. The interaction of α-synuclein with PSEN1 was detected in post-mortem brain tissue from cognitively normal cases and was significantly increased in tissue from cases with dementia with Lewy bodies and familial Alzheimer's disease associated with known PSEN1 mutations. We confirmed an increased interaction of PSEN1 and α-synuclein in cell lines expressing well characterized familial Alzheimer's disease PSEN1 mutations, L166P and delta exon 9, and demonstrated that PSEN1 mutations associate with increased membrane association and accumulation of α-synuclein. Our data provides evidence of a molecular interaction of PSEN1 and α-synuclein that may explain the clinical and pathophysiological overlap seen in synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and some forms of Alzheimer's disease.
authors.affiliation: 1 MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Winslow
authors.affiliation: 2 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Moussaud
authors.affiliation: 1 MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Zhu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Post
authors.affiliation: 1 MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Post
authors.affiliation: 2 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: 1 MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA mclean.pamela@mayo.edu oberezovska@mgh.harvard.edu.
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.affiliation: 2 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA mclean.pamela@mayo.edu oberezovska@mgh.harvard.edu.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016466:CHO Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex; D003412:Cricetulus; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D020961:Lewy Body Disease / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1; D051844:alpha-Synuclein; D005982:Glutathione Transferase; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Lewy body; Parkinson’s disease; ageing; dementia; presenilin; α-synuclein