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.

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

“…Tau may interact directly with postsynaptic signaling complexes, regulate glutamatergic receptor content in dendritic spines (65), and influence targeting and function of synaptic mitochondria (66,67). Tau-targeted immunotherapy can reduce tau pathologies and synapse loss (68), indicating that the toxic effects of tau may be reversible.…”

Roles of tau protein in health and disease

“…Tau is cleaved at D13 by caspase-6 and at D421 by caspase-3[30, 125, 151, 182, 208, 330, 369, 412]NH2-tauQ26-R230Enriched in synaptosomal mitochondria in AD brainInduced by apoptosis in SHSY-5Y neuroblastoma cells. Present in hippocampus in AD11 transgenic mice which have chronic NGF deprivation during adulthood and display AD-like molecular and behavioural phenotypes[7–10, 24, 89, 90, 404]E45-R23017Detected in AD, ALS, and control brainGenerated in neurons by exposure to Aβ or by thapsigargin-mediated inhibition of autophagy. Induces neurodegeneration when expressed in mice.…”

New methods for monitoring mitochondrial biogenesis and mitophagy in vitro and in vivo

“…9,10 Removal of damaged mitochondria via mitophagy is essential for prevention of cellular dysfunction and death. Impaired mitophagy has been implicated in many neurodegenerative diseases such as Parkinson's disease, 11 Alzheimer's disease, 12,13 amyotrophic lateral sclerosis (ALS), 14,15 and Huntington's disease. 16,17 In addition, mitophagy may also protect the liver during acetaminophen overdose and alcoholic liver disease by removing damaged mitochondria.…”