Intracellular aggregation of tau into neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD) and is known to correlate with synapse loss and neurodegeneration. However, the mechanisms that drive tau aggregation are still unknown.
In Neuron, a team co-led by Bradley T. Hyman, MD, PhD, director of the Massachusetts Alzheimer Disease Research Center at Massachusetts General Hospital, reports multiple lines of in vitro and in vivo evidence that tau disrupts communication between the nucleus and cytoplasm of neurons. Specifically, it interacts with components of nuclear pore complexes (NPCs). Targeting those interactions could be a new therapeutic strategy for AD.
The researchers explain that NPCs, located on nuclear membranes, consist of multiple copies of 30 different proteins called nucleoporins (Nups). These molecular assemblies control the trafficking of RNA and larger proteins between the nucleoplasm and the cytoplasm.
The entry and exit of this “cargo” are controlled by a pair of proteins. During import, a molecule is released into the nucleus when its transport receptor interacts with intranuclear RanGTP. During export, a molecule is released into the cytoplasm upon hydrolysis of RanGTP to generate RanGDP. The nucleocytoplasmic gradient of RanGTP and RanGDP thus defines the directionality of nucleocytoplasmic transport.
Disruption of the Ran gradient can cause toxicity and cell death. In previous research, disrupted nucleocytoplasmic transport in neurons was detected in amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington’s disease and normal aging. However, the involvement of tau in these conditions, as well as its more general role in nucleocytoplasmic transport, had not been studied.