Neuronal microtubule regulation and aging

PROJECT SUMMARY
(Neuronal microtubule regulation and its autonomous and non-autonomous effects on aging)
Aging is the greatest risk factor for developing neurodegenerative diseases including Alzheimer's Disease
(AD). Neuronal aging, defined as a progressive loss of function and structure, predisposes neurons to
degeneration. The importance of microtubule (MT) regulation in neurons is underscored by the critical role of
MT-associated proteins, e.g. tau and tau-like proteins, whose dysfunction leads to neurodegeneration.
Surprisingly, little is known about the role of MTs in the normal aging process. MT regulation is involved on
several levels of neuronal function and maintenance of structure, and MT regulation also appears to be a
general downstream indicator and effector in age-dependent neurodegeneration. The cause and effect
relationship between MT defects and cellular dysfunction is not clear. In C. elegans, it has been demonstrated
that mutations in protein with tau-like repeats (ptl-1), an ortholog of tau/MAP2/MAP4, leads to defective
neuronal function and an accelerated occurrence of age-associated morphological changes. On the other
hand, it has also been shown that mutations in other MT regulators delay the onset of age-related changes.
These data show defects in MTs are not only associated with, but also contribute to, neuronal aging. The
goals of this proposed study are to define changes in MT status associated with neuronal aging and to
characterize mechanisms by which MT defects affect neuronal function. Preliminary data indicate mutations in
multiple MT regulators are sufficient to influence lipid metabolism and lifespan. The central hypothesis is
preservation of MT polymerization in neurons delays neuronal aging and promotes longevity through gap
junctions. In Aim 1, we will test whether loss of MT polymerization causes neuronal aging. In Aim 2, we will
test whether neuronal MT perturbation regulates longevity and peripheral lipid metabolism via gap junctional
signaling. Confocal imaging, molecular, biochemical and C. elegans genetic approaches will be used to fulfil
these aims. Data generated from this proposal will not only increase our understanding of the roles played by
MT regulation in the neuronal and organismal aging, but also potentially lead to novel targets to delay aging
and its associated diseases.

Grant Number: 5R01AG071591-04
NIH Institute/Center: NIH
Principal Investigator: Lizhen Chen