Page:Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins.pdf/1

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OPEN

Received: 07 January 2016 Accepted: 04 April 2016 Published: 21 April 2016

Xia-Chun Li, Yu Hu, Zhi-hao Wang, Yu Luo, Yao Zhang, Xiu-Ping Liu, Qiong Feng, Qun Wang, Keqiang Ye, Gong-Ping Liu & Jian-Zhi Wang

'''Intracellular accumulation of tau protein is hallmark of sporadic Alzheimer’s disease (AD), however, the cellular mechanism whereby tau accumulation causes neurodegeneration is poorly understood. Here we report that overexpression of human wild-type full-length tau (termed htau) disrupted mitochondrial dynamics by enhancing fusion and induced their perinuclear accumulation in HEK293 cells and rat primary hippocampal neurons. The htau accumulation at later stage inhibited mitochondrial functions shown by the decreased ATP level, the ratio of ATP/ADP and complex I activity. Simultaneously, the cell viability was decreased with retraction of the cellular/neuronal processes. Further studies demonstrated that htau accumulation increased fusion proteins, including OPA1 and mitofusins (Mfn1, Mfn2) and reduced the ubiquitination of Mfn2. Downregulation of the mitofusins by shRNA to ~45% or ~52% of the control levels attenuated the htau-enhanced mitochondrial fusion and restored the functions, while downregulation of OPA1 to ~50% of the control level did not show rescue effects. Finally, abnormal mitochondrial accumulation and dysfunction were also observed in the brains of htau transgenic mice. Taken together, our data demonstrate that htau accumulation decreases cell viability and causes degeneration via enhancing mitofusin-associated mitochondrial fusion, which provides new insights into the molecular mechanisms underlying tauopathies.'''

Abnormal accumulation of wild-type human tau proteins is a hallmark of sporadic Alzheimer disease (AD . Expression of full-length human tau alone causes intracellular tau pathologies and behavioral deficits in mice, while turning off tau expression attenuates the pathologies . Reduction of endogenous tau also ameliorates memory deficits caused by β-amyloid (Aβ) . These data suggest a crucial role of tau accumulation in neurodegeneration and memory loss. However, how intracellular accumulation of the wild-type tau impairs the cells’ function and eventually leads to neurodegeneration and memory impairments is currently not fully understood.

Mitochondrial dysfunction is an early pathological event of AD, , and abnormal mitochondrial morphology and distribution are detected in the postmortem AD brains and their fibroblasts ,. Recent studies suggest that there is an intrinsic link between human tau and mitochondria. For instance, an N-terminal truncated tau (20–22kDa) is largely enriched in mitochondria of the AD brains and its amount in nerve terminal fields correlates with the pathological synaptic changes. Mitochondrial dysfunction is also detected in P301L tau transgenic mice. Deregulation of mitochondrial complex I with aging is tau-dependent. Tau phosphorylation can antagonize cell apoptosis with the mechanisms involving Bcl-2 and caspase-3 in mitochondria, , while expression SCIENTIFIC REPORTS