https://t.co/C2wLRnCv0m I am excited to announce our work on how myelin loss culminates in neurodegeneration has been published at Nature Communications. While I have previously covered our findings as a preprint in more detail below, our key findings are:

New work from Yasmine Kamen shows that differentiating oligodendrocytes are filled with the zymogen procaspase-3. This provides a specific marker for new oligodendrocytes and suggests a role for this pathway in oligodendrocyte fate decisions. https://t.co/qGx23d7Dxp

Our work was recently covered by the National MS Society if you are looking for a more lay summary of the results and its implications. https://t.co/vMDfj3tX25

And the completion of this story was only possible because of all the help from the most amazing @Anya_A_Kim and Björn Neumann in the Franklin lab!🥰

3. Remyelination suppresses activation of DLK in neurons and safeguards them from degeneration. In conclusion, demyelinated neurons can be protected either by promoting remyelination or blocking neuronal DLK signaling. Thanks to all the coauthors who made this work possible!

1. Loss of demyelinated neurons in the retina requires activation of neuronal injury signaling mediated by the axonally-expressed protein Dual Leucine zipper Kinase (DLK). 2. DLK knockout or inhibitors protect neurons from degeneration.

This has been the culmination of many years of work from myself and the coauthors of this manuscript, without which this work would have been impossible. Thank you all so much for your help!

What does all this mean? We can protect demyelinated neurons from loss in two ways – by promoting remyelination or by inhibiting DLK. Notably, even a relatively small degree of remyelination reduces apoptosis.

Inhibition of DLK by remyelination, genetic knockout of DLK, or a drug blocking DLK activity stops the activation of c-Jun in demyelinated neurons and spares them from apoptosis.

How do neurons degenerate? There is increased transcription of genes downstream of a protein sensitive to axonal damage called dual leucine zipper kinase (DLK). DLK sends a signal to the nucleus activating a transcription factor called c-Jun.

What does a failure to regenerate myelin do to neurons? We find that remyelination failure results in increased neuronal apoptosis, whereas remyelination protects neurons from apoptosis and axonal damage.

They work by removing Myrf from oligodendrocytes, which causes demyelination and loss of oligodendrocytes. To block remyelination, we extend the knockout of Myrf to oligodendrocyte precursor cells, which blocks their differentiation at an intermediate stage.

Leveraging my supervisor’s (Ben Emery’s) discovery of the transcription factor Myrf, we develop and characterize two demyelinating models which either permit or block subsequent remyelination.

Remyelination is often efficient in the models we use of demyelination. This makes it challenging to identify how neurons lacking myelin might degenerate.

Demyelination is the hallmark of multiple sclerosis (MS). Neurons receive support from cells that produce myelin, called oligodendrocytes. It is this loss of this support during demyelination that is thought to cause neurodegeneration and progressive disability in MS.

Very excited to share our preprint on how chronic myelin loss (demyelination) injures neurons and how we may be able to mitigate neurodegeneration in demyelinating diseases like MS https://t.co/Oj6xb3KaJf Check out the thread 👇 for more details.

Why is age the main risk for Alzheimer’s disease? Mouse models reveal that the loss of myelin integrity is causally linked to enhanced plaque deposition. Great work by ⁦@ConstanzeDepp⁩, ⁦@TingSun_MPINAT⁩ et al. in Nature

Excited to see our preview of the great work from Su et al. published in Neuron on how astrocyte endfeet regulate myelination. Their work gives an excellent insight into how astroycte-oligo interactions shape myelination. https://t.co/uSTuBuhSZg https://t.co/rgwrDAdZsu

A great opportunity 👇

Absolute pleasure to attend and present at ⁦@cshlmeetings⁩ Glia Meeting!