Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease.
Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.
Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, AP- HP, Paris, France; Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013 Paris, France; Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Université Libre de Bruxelles, B-1070 Brussels, Belgium.
Kunie
K
Ando
Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, AP- HP, Paris, France; Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013 Paris, France.
Karen
K
Tomimura
Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, AP- HP, Paris, France.
Véronique
V
Sazdovitch
Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Université Libre de Bruxelles, B-1070 Brussels, Belgium.
Valérie
V
Suain
Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Université Libre de Bruxelles, B-1070 Brussels, Belgium.
Zehra
Z
Yilmaz
Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Université Libre de Bruxelles, B-1070 Brussels, Belgium.
Michèle
M
Authelet
Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013 Paris, France.
Marième
M
Ndjim
Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Université Libre de Bruxelles, B-1070 Brussels, Belgium.
Cristina
C
Vergara
Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, AP- HP, Paris, France; Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013 Paris, France.
Mounir
M
Belkouch
Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013 Paris, France.
Marie-Claude
MC
Potier
Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, AP- HP, Paris, France; Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013 Paris, France. Electronic address: charles.duyckaerts@aphp.fr.
Charles
C
Duyckaerts
Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Université Libre de Bruxelles, B-1070 Brussels, Belgium. Electronic address: jpbrion@ulb.ac.be.
Jean-Pierre
JP
Brion
D000544:Alzheimer Disease / Q000378:metabolism*; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism; D006801:Humans; D034041:Monomeric Clathrin Assembly Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D020774:Pick Disease of the Brain / Q000378:metabolism*; D011030:Pneumothorax / Q000378:metabolism*; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism; D024801:Tauopathies / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
D000071183:Autophagy-Related Proteins; D002966:Clathrin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D016875:tau Proteins
Alzheimer's disease; Autophagy; Beclin-1; Corticobasal degeneration; Diffuse Lewy body disease; FTLD-MAPT; FTLD-TDP; LC3; NFTs; PICALM; Pick disease; Progressive supranuclear palsy; Tau