Mutations in the microtubule-binding protein tau cause the protein to aggregate in neurodegenerative diseases such as some forms of frontotemporal dementia—but many conditions evince tau tangles in the absence of tau mutations. Scientists know that mutant tau interferes with axonal transport. The explanation for wild-type tau tangles may be that transport deficiencies, in turn, cause tauopathy. In the May 6 Journal of Neuroscience, scientists from the University of California, San Diego, report that when they interfered with transport in mice, tau became hyperphosphorylated. The authors suggest that impaired axonal transport could be a common mechanism leading to tau tangles in the handful of diseases so far defined as tauopathies.
Tangled tau features in nine known tauopathies (reviewed in Hernndez and Avila, 2007), and axonal transport defects are common in neurodegenerative disease (reviewed in De Vos et al., 2008). In all these neurodegenerative diseases, axonal transport is abnormal at some point, said Virgil Muresan of the University of Medicine and Dentistry of New Jersey in Newark, who was not involved with the current study. The problem is whether axonal transport is a cause, a consequence, or somehow a facilitating factor.
In tauopathies, it may be all three. Joint first authors Toms Falzone, currently at UCSD, but soon to move to the University of Buenos Aires in Argentina; Gorazd Stokin of the University Psychiatric Hospital in Ljubljana, Slovenia; principal investigator Lawrence Goldstein of UCSD; and colleagues had reason to suspect that disruption of axonal transport could lead to tau pathology. Previously, Goldstein’s lab found axonal defects preceded amyloid-β pathology in a mouse model of AD as well as in people with the disease, suggesting such defects might precede tau pathology, too (ARF related news story and Stokin et al., 2005). The group has also linked axonal transport to stress response kinases, which could phosphorylate tau (Cavalli et al., 2005)—hyperphosphorylated tau is associated with tauopathy.
The authors interfered with axonal transport in mice by deleting kinesin light chain 1 (KLC1), a subunit of a microtubule motor that is required for normal localization of, among other proteins, APP in mice. As the KLC1-negative animals aged, they exhibited axonal degeneration in the corpus callosum and anterior commissure, as well as increased neurofilament phosphorylation in the hippocampus compared to wild-type animals. In the spinal cord, the mutant mice had more proximal swellings and less white matter than control mice.
As the scientists predicted, the mutant animals also had tau troubles. A panel of antibodies to phosphorylated tau stained the mutant spinal cord axons and ventral motor neuron roots much more darkly than wild-type sections. There was three times as much hyperphosphorylated tau in large, filamentous structures in the giant axons and neuronal roots of mutant animals.
I love the science; it’s the relevance to human AD I would question, said Peter Davies of the Feinstein Institute in Long Island, New York, who was not involved with the study. Mouse tau, unlike the human protein, has little tendency to form tangles, and engineered mouse tauopathy models do not exactly mirror human disease. You end up seeing pathology in places where you don’t see pathology in humans, Davies said. Mice tend to show tau pathology in the spinal cord, for example, whereas in Alzheimer disease the tangles are primarily in the brain.
The discovery still has relevance to tauopathies, Falzone said, even if the pathology is not exactly the same as in human diseases. Our work reveals the biochemical consequences of interfering directly with such transport pathways, he wrote in an e-mail to ARF. If transport defects occur early in some diseases, the consequences we report are likely to play an important role in progression. The mice do show AD-like hippocampal pathology. In addition, amyotrophic lateral sclerosis with frontotemporal dementia includes spinal cord tau pathology, so the model may be relevant to that disease.
The axonal transport defect alters tau, the authors suggest, via c-Jun N-terminal stress kinase (JNK). Falzone and colleagues found a 75 percent increase in JNK activation in the brains of the KLC1 knockout animals. Other tau-related kinases were unaffected by the KLC1 mutation. We suggest that defects in axonal transport can lead to a chronic axonal JNK-stress pathway in which tau protein may get hyperphosphorylated and further impair axonal transport by disrupting the microtubule network and blocking axonal highways, launching an autocatalytic spiral culminating in neurodegeneration, he wrote.
That could be true, Muresan said, but he is not fully convinced that JNK mediates a specific signal between axonal transport and tau. Maybe it is a general stress pathway that is triggered here, and deficient axonal transport is just one way you trigger this cascade of events, he said. In response, Falzone noted that activated JNK colocalized with the swollen axons in the mutant mice, and that activated JNK is also associated with neurofibrillary tangles in human AD, further evidence that JNK might trigger tauopathy.
We believe this is a common mechanism among tauopathies, Falzone said. There are nine known diseases of hyperphosphorylated, aggregated tau, often linked to dementia. Tauopathies include Pick disease, progressive supranuclear palsy, Guam parkinsonism dementia complex, and Niemann-Pick-disease type C. Research published online in the May 5 PNAS adds another tauopathy, Sanfilippo syndrome type B, to the roster. First author Kazuhiro Ohmi, senior authors Stanislav Karsten and Elizabeth Neufeld, and colleagues at the University of California, Los Angeles, discovered phosphorylated tau aggregates in the brains of a mouse model for this disease. Like Niemann-Pick, Sanfilippo is a lysosomal storage disease; it causes mental retardation and dementia, and death in the teens.
In Falzone’s model, tau pathology causes transport defects, transport defects cause tauopathy, and a cell can enter the loop at either point. In AD, he suggested, APP can disrupt transport, leading to tau tangles. Next, Falzone hopes to learn more about the pathway between tauopathy and axonal transport, as well as to confirm the link by showing that in other animals with tauopathy, interfering with axonal transport intensifies disease. It is going to be really important to show that transport defects can lead to an increase in the pathology in tauopathy models, Falzone said.
Falzone TL, Stokin GB, Lillo C, Rodrigues EM, Westerman EL, Williams DS, Goldstein LSB. Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects. J Neurosci. 2009 May 6;19(18):5758-67. Abstract
Ohmi K, Kudo LC, Ryazantsev S, Zhao HZ, Karsten SL, Neufeld EF. Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proc Natl Acad Sci U S A. 2009 May 5. Abstract
To view commentaries, primary articles and linked stories, go to the original posting on Alzforum.org here.
Copyright © 1996–2018 Biomedical Research Forum, LLC. All Rights Reserved.Share this: