EMBO Fellows Meeting 2012

Bogdan Beirowski
EMBO Fellows Meeting 2012
Sirtuin 2 in Schwann cells modulates peripheral myelination through Par-3 polarity
signaling
Abstract
Schwann cells (SCs) are a type of supportive tissue in the vertebrate peripheral nervous system that associate
with axons to produce a multilayered membrane known as myelin. The highly orchestrated process of myelin
formation occurs during development and after nerve injury in the peripheral nervous system. Myelin sheaths
allow neuronal signals to pass rapidly along nerves, crucial for normal movement and sensation. Impeded
myelination underlies several peripheral neuropathies, neurological disorders characterized by abnormal nerve
function. While some disease genes and mechanisms underlying inherited neuropathies have been elucidated
in the last decades, the processes leading to neuropathies secondary to metabolic derangements such as
diabetes remain mostly enigmatic. The compromised myelin formation and axon damage in these conditions
could be due to changes in molecular pathways that are regulated by SC energy metabolism. We used global
expression profiling to examine peripheral nerve myelination and identified the deacetylase Sirt2 as a protein
likely to be involved in myelination. Sirt2 is a member of the conserved sirtuin family of NAD+ dependent
deacetylases whose activity to control a multitude of molecular processes is determined by the energetic and
metabolic state of the cell. Abnormal sirtuin activity is believed to play a significant role in metabolic diseases
like diabetes, and manipulation of sirtuin function has promising potential as therapy. Here, we show that Sirt2
expression in SCs is correlated with that of structural myelin components during both developmental
myelination and remyelination after nerve injury. We discovered that Sirt2 deacetylates Par-3, a master
regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex
signaling component aPKC in SCs. Consistent with the idea that proper establishment of SC polarity is
necessary for normal wrapping of axons with myelin, we found that manipulation of Sirt2 levels, and the
polarity pathway it affects, results in myelination deficits in vivo. In conclusion, we describe a novel type of
molecular crosstalk in myelin-forming SCs that involves Sirt2 and a central polarity pathway. This finding may
help to improve our understanding of mechanisms underlying neuropathies characterized by impaired SC
myelination and metabolic disease. Moreover, our study raises the intriguing possibility that the identified
Sirt2/Par-3/aPKC pathway provides a link between changes in myelination and nutritional alterations, aging,
and physical exercise.
Laboratory of Jeffrey Milbrandt
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
14-17 June 2012, Heidelberg, Germany