Nerve cell pruning leads to disease
Mechanisms meant to grow our brain network may be malfunctioning in neurodegenerative diseases.
Research into neurodegenerative disease has traditionally concentrated on the death of nerve cells. But now, science is certain that in most cases nerve cell death represents the final event of an extended disease process. Studies show that protecting nerve cell bodies from death has no impact on disease progression—whereas blocking the preceding event of axon breakdown has a significant results.
The new study by researchers at The Neuro of Montreal, Canada, an academic medical centre dedicated to neuroscience, shifts the focus to the loss or degeneration of axons, the nerve-cell ‘branches’ that receive and distribute neurochemical signals among neurons.
During early development, axons are pruned to ensure normal growth of the nervous system. Emerging science suggests that this pruning process becomes reactivated in neurodegenerative diseases, leading to the abnormal loss of axons and dendrites.
Axon pruning in development is significantly influenced by proteins called caspases.
“The idea that caspases are even involved in axonal degeneration during development is very recent” said Dr. Philip Barker, a principal investigator at The Neuro and senior author of the study.
Dr. Barker and his colleagues show that the activity of certain ’executioner’ caspases (caspase-3 and caspase-9) induce axonal degeneration and that their action is suppressed by a protein termed XIAP (X-linked inhibitor of apoptosis).
“We found that caspase-3- and -9 play crucial roles in axonal degeneration and that their activities are regulated by XIAP. XIAP acts as a brake on caspase activity and must be removed for degeneration to proceed” added Dr. Barker.
This balancing act between caspases and XIAP ensure that caspases do not cause unnecessary or excessive destruction. However, this balance may shift during neurodegenerative disease.
“If we understand the pathways that regulate XIAP levels, we may be able to develop therapies that reduce caspase-dependent degeneration during neurodegenerative disease.”
This research is published in Cell Reports. It points to pathways and targets for new therapies in Alzheimer’s, Parkinson’s, ALS and other neurodegenerative diseases affecting millions of people world-wide.
Our knowledge of the destructive events that regulate axonal degeneration is rudimentary. Here, we examine the role of caspases and their endogenous inhibitor, the X-linked inhibitor of apoptosis protein (XIAP), in axonal degeneration of dorsal root ganglion (DRG) axons. We show that caspase-3, caspase-6, and caspase-9 are present in axons and are cleaved upon nerve growth factor (NGF) withdrawal. We observed that caspase-3 activity is high in NGF-withdrawn axons and that CASP3−/− axons are protected from degeneration. XIAP−/− DRG sensory neurons degenerate more rapidly and contain more active caspase-3 than their wild-type counterparts, indicating that axonal caspases are normally regulated by XIAP. Importantly, axonal XIAP levels drop sharply after NGF withdrawal; if XIAP levels are maintained by overexpression, axonal caspase-3 activation and axonal degeneration are suppressed. Finally, we show that XIAP−/− embryos have stunted dermal innervation. We propose that XIAP-mediated caspase inhibition plays an important role in regulating morphogenic events that shape the nervous system during development.
The Montreal Neurological Institute and Hospital — The Neuro, is a unique academic medical centre dedicated to neuroscience. Founded in 1934 by the renowned Dr. Wilder Penfield, the Neuro is recognized internationally for integrating research, compassionate patient care and advanced training, all key to advances in science and medicine. The Neuro is a research and teaching institute of McGill University and forms the basis for the Neuroscience Mission of the McGill University Health Centre. Neuro researchers are world leaders in cellular and molecular neuroscience, brain imaging, cognitive neuroscience and the study and treatment of epilepsy, multiple sclerosis and neuromuscular disorders. For more information, visit theneuro.com
Original press releas: http://www.mcgill.ca/channels/news/everything-moderation-excessive-nerve-cell-pruning-leads-disease-230995