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Role of secretases in myelination

Final Report Summary - SECRETASES & MYELIN (Role of secretases in myelination)

Demyelinating hereditary neuropathies are a group of rare disorders in which the defect is due to problems in the synthesis and maintenance of myelin, the fatty substance wrapped around the nerves. These diseases are due to mutations in more than 70 genes and they result in muscle weakness, altered sensation and pain. These neuropathies can affect children, all members in a family, and in the most severe forms lifespan can be shortened. For all these reasons there is no effective treatment for this class of disorder and the study of the mechanisms controlling the synthesis of myelin is essential to identify novel avenues of intervention.
We and other groups previously characterized an important growth factor, called Neuregulin 1 type III that controls the formation of myelin in the nerves. We also recently showed that this growth factor is processed on the nerves by other proteins. These molecules, called secretases, act as “biological scissors” and their cleavage could either promote or inhibit the activity of this growth factor regulating myelin formation. In addition we also recently found that these “scissors” induce the expression of other molecules that promote myelin formation and maintenance in the nerves.
The main objective of the proposed studies was to investigate the role of secretases in Peripheral Nervous System (PNS) myelination. Specifically we proposed to use a combination of cell culture techniques and in vivo animal models that allows us to study the molecular mechanisms regulating PNS myelin formation and maintenance.
Collectively, our study suggests that Neuregulin 1 type III controls myelination in multiple ways and we provide data supporting the existence of a novel pathway whose modulation could be beneficial for the treatment of peripheral demyelinating neuropathies.

Elucidating the mechanisms controlling NRG1 type III expression and activity and identifying how secretases are involved in PNS meylination, will provide important insights into the mechanisms controlling regulation of myelination and potentially of neuronal survival. Of note, the secretases implicated in NRG1 type III processing are fundamental also in the pathogenesis of Alzheimer disease and regulate several other biological events. Further, recent studies have implicated glial cells and neuron communications in the pathogenesis of many neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson disease and spinocerebellar ataxia. All these studies have shown that altered neuron-glia signaling leads to impaired synaptic transmission. This non-cell autonomous mechanism is common to many neurodegenerative diseases in which the expression of a mutated protein in non-neuronal cells causes toxicity and neuronal cell death. How glial cells are involved in these non-cell autonomous mechanisms is still an unresolved question. Clarifying the interaction between glia and neurons is thus necessary for an appropriate understanding of the mechanisms regulating many if not all neurodegenerative diseases and more importantly, to develop efficient therapeutic treatments. This is particularly relevant in order to significantly reduce the cost of demyelinating pathologies, diminish the social impact of these diseases and, more importantly, improve the quality of life of individuals affected by demyelinating disorders and possibly by neurodegenerative diseases.