Clinical issue

The molecular processes underlying axon degeneration in many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, are only partially understood. Approaches that block or reverse these conditions are urgently needed. LKB1 (also known as STK11) is a protein kinase and tumour suppressor with multiple functions; its downstream targets include AMP-activated protein kinase (AMPK) and sporadic Alzheimer’s disease (SAD)-A/B kinase (also known as Brsk1/2). Studies in worms indicate that LKB1 controls neuronal polarity by affecting axon differentiation, in part through interacting with SAD-A/B kinase. However, the role of LKB1 in the mammalian CNS, and its potential involvement in the pathology of neurodegenerative diseases, has not been well characterized.

Results

In this study, the authors investigate mice conditionally lacking LKB1 in the spinal cord, some parts of the brain and endocrine pancreas, and show that LKB1 is essential in the CNS to prevent neurodegeneration and eventual paralysis and death in mice. At the cellular level, lack of LKB1 in neurons led to abnormal microtubule structures and a decrease in neurofilament and tubulin expression. Surprisingly, one of the key downstream targets of this enzyme, AMPK, seems not to be the mediator of the required signals, whereas another LKB1 target, SAD-A/B kinase, and its subsequent phosphorylation of tau protein are involved in preventing axonal degeneration.

Implications and future directions

These results establish a role for LKB1 in promoting neuronal survival and the control of motor function in an in vivo mammalian system. Approaches that enhance the activity of LKB1 or its relevant downstream targets might provide a novel therapeutic strategy for preventing or reversing the pathology of neurodegenerative diseases.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.