title: NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease.
abstract: Disarrangement in functions and quality control of mitochondria at synapses are early events in Alzheimer's disease (AD) pathobiology. We reported that a 20-22 kDa NH2-tau fragment mapping between 26 and 230 amino acids of the longest human tau isoform (aka NH2htau): (i) is detectable in cellular and animal AD models, as well in synaptic mitochondria and cerebrospinal fluids (CSF) from human AD subjects; (ii) is neurotoxic in primary hippocampal neurons; (iii) compromises the mitochondrial biology both directly, by inhibiting the ANT-1-dependent ADP/ATP exchange, and indirectly, by impairing their selective autophagic clearance (mitophagy). Here, we show that the extensive Parkin-dependent turnover of mitochondria occurring in NH2htau-expressing post-mitotic neurons plays a pro-death role and that UCHL-1, the cytosolic Ubiquitin-C-terminal hydrolase L1 which directs the physiological remodeling of synapses by controlling ubiquitin homeostasis, critically contributes to mitochondrial and synaptic failure in this in vitro AD model. Pharmacological or genetic suppression of improper mitophagy, either by inhibition of mitochondrial targeting to autophagosomes or by shRNA-mediated silencing of Parkin or UCHL-1 gene expression, restores synaptic and mitochondrial content providing partial but significant protection against the NH2htau-induced neuronal death. Moreover, in mitochondria from human AD synapses, the endogenous NH2htau is stably associated with Parkin and with UCHL-1. Taken together, our studies show a causative link between the excessive mitochondrial turnover and the NH2htau-induced in vitro neuronal death, suggesting that pathogenetic tau truncation may contribute to synaptic deterioration in AD by aberrant recruitment of Parkin and UCHL-1 to mitochondria making them more prone to detrimental autophagic clearance.
authors: Institute of Translational Pharmacology (IFT) - National Research Council (CNR), Via Fosso del Cavaliere 100-00133, Rome, Italy.
authors: V
authors: V
authors: Corsetti
authors: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: F
authors: F
authors: Florenzano
authors: Institute of Biomembranes and Bioenergetics (IBBE)-CNR, Via Amendola 165/A, 70126 Bari, Italy.
authors: A
authors: A
authors: Atlante
authors: Institute of Biomembranes and Bioenergetics (IBBE)-CNR, Via Amendola 165/A, 70126 Bari, Italy.
authors: A
authors: A
authors: Bobba
authors: Institute of Cellular Biology and Neuroscience (IBCN)-CNR, IRCSS Santa Lucia Foundation Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: M T
authors: MT
authors: Ciotti
authors: Institute of Cellular Biology and Neuroscience (IBCN)-CNR, IRCSS Santa Lucia Foundation Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: F
authors: F
authors: Natale
authors: Institute of Cellular Biology and Neuroscience (IBCN)-CNR, IRCSS Santa Lucia Foundation Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: F
authors: F
authors: Della Valle
authors: Institute of Cellular Biology and Neuroscience (IBCN)-CNR, IRCSS Santa Lucia Foundation Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: A
authors: A
authors: Borreca
authors: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: A
authors: A
authors: Manca
authors: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: G
authors: G
authors: Meli
authors: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: C
authors: C
authors: Ferraina
authors: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: M
authors: M
authors: Feligioni
authors: Institute of Cellular Biology and Neuroscience (IBCN)-CNR, IRCSS Santa Lucia Foundation Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: S
authors: S
authors: D'Aguanno
authors: UCO Pathological Anatomy and Histopathology Unit, Cattinara Hospital Strada di Fiume 447, 34149 Trieste, Italy and.
authors: R
authors: R
authors: Bussani
authors: Institute of Cellular Biology and Neuroscience (IBCN)-CNR, IRCSS Santa Lucia Foundation Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: M
authors: M
authors: Ammassari-Teule
authors: Department of Medical, Surgical and Health Science, University of Trieste, Strada di Fiume 449, 34149 Trieste, Italy.
authors: V
authors: V
authors: Nicolin
authors: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
authors: P
authors: P
authors: Calissano
authors: Institute of Translational Pharmacology (IFT) - National Research Council (CNR), Via Fosso del Cavaliere 100-00133, Rome, Italy European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy g.amadoro@inmm.cnr.it.
authors: G
authors: G
authors: Amadoro
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D006367:HeLa Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D021381:Protein Transport; D017208:Rats, Wistar; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: C054369:MAPT protein, human; D024101:Mitochondrial Proteins; C482860:UCHL1 protein, human; D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D043222:Ubiquitin Thiolesterase