neuro

Myelin

- is the membrane of specialized cells called oligodendrocytes. Myelin is not only a "passive" insulation of the nerve "fiber", but also as very active interface to exchange reagents with the axon, thereby actively participating to axonal function
Oligodendrocyte
Myelinating Oligodendrocyte

Myelin damage

can be detected in:

- Neurological Disorders of the Adult Brain including toxic, metabolic or ischemic conditions as well as in inflammatory conditions, such as Multiple Sclerosis.

- Pediatric pathologies related to genetic defects or nutritional (i.e. low iron diet, vitamin B12 deficiency) and hormonal (i.e. hypothyroidism) deficiencies in the mother, as well as to developmental disorders of the preterm infant.

- Psychiatric disorders, including: depression, schizophrenia and autism
To understand what steps are important for the generation of oligodendrocytes one project involves the study of the molecular events responsible for the formation of these cells during development. A follow up study is to ask whether the same events are reactivated in the adult brain after injury. Developmental myelination is studied in mouse and rat models during the first two post-natal weeks, a temporal window which corresponds to human mid-gestation. Molecules and genes are then analyzed in adult animals and in human cells and brain specimens. A second area of study is axonal damage, since this is a critical event to target for repair. We are using multiple approaches to target this issue, including live imaging, animal models and human cells. An overall description of these studies is presented below. Detailed information can be found in the publication links.
Research Project 1:
The role of the environment in modulating gene expression: epigenomics, development and disease

 

Epigenetics refers to external factors affecting gene expression independently of changes in DNA sequence.

Epigenetics and development
All the cells in our bodies share the same genetic information so each one must define its own identity by making sure that only genes involved in its specific function are expressed. My lab has been investigating how oligodendrocytes acquire their identity during development. We showed that the identity of these myelin-making cells requires the inactivation of genes that prevent myelin gene expression. We then demonstrated that the process of myelin repair in the adult brain recapitulates developmental events and is severely impaired with ageing. We are therefore exploring the idea that myelin regeneration in the adult brain could be achieved by finding ways of eliminating the expression of genes interfering with myelin synthesis. An interesting finding of the lab that was published last year is that social experiences modulate gene expression in oligodendrocyte by affecting chromatin.

Epigenetics and Disease
We have focused our research interest on MS. The model being tested by the lab is that genetics provides the susceptibility to develop the disease (for instance by creating an immune system that is more prone to "attack" specific molecules or specific cell types). The environment and life style, however, has the ability to tweak this propensity by changing the expression of certain genes. In other words, the manifestation of the disease is the result of a combination between genetic predisposition and environmental influences including sun exposure, smoking, possibly diet and lifestyle, viral infections and microbial populations. Here is a blog from the ALS meeting 2013.

Guts and Brains
We have recently started a very exciting study in the characterization of the microbiome in patients with MS and we hope that this interesting venue of analysis will provide potential new therapeutic intervention tools. Read more about the microbiome studies.

Research Project 2:
Molecular mechanisms of repair in demyelinating and dysmyelinating disorders using animal models
and patient-derived induced pluripotent stem cells
myelinated fiber dapi-and-h&e
Myelin damage is detected in a wide variety of disorders in children and adults. Myelin malfunction in children may be caused by genetic deficits, maternal nutritional deficiencies, vascular problems, prematurity. The main cause of demyelination in the adult brain is an immunological attack to myelin, as observed in Multiple Sclerosis, and the demyelination observed after traumatic injury to the brain or the spinal cord. Recovery of function can be obtained only after progenitors differentiate into myelinating oligodendrocytes and form new myelin. We previously defined the critical role played by molecules called "histone deacetylases" (i.e. HDACs) in myelin formation during development and showed that administration of pharmacological inhibitors of HDAC to developing rats or fish inhibited developmental myelination. We have recently extended our work to the investigation of repair of damaged myelin in the adult brain. Using chromatin immunoprecipitation and confocal analysis of brain slices, we are characterizing the response of adult progenitors to toxic demyelination of white matter tracts in the mouse brain and spinal cord. We have also started to define whether similar changes occur in induced pluripotent stem cells derived from patients' skin. The overall goal is to define novel molecular targets to promote repair in demyelinating disorders of the adult brain (i.e. Multiple Sclerosis) and in pediatric diseases characterized by demyelination.
Research Project 3:
nderstanding the mechanism of clinical disability and disease progression:
axonal damage and neurodegeneration
project3 project3 project3

The actual mechanism of neurodegeneration (i.e. damage to axons and loss of neurons) is still debated and its elucidation is critical for development of effective therapies. It was traditionally believed that damage was the direct consequence of 'loss of myelin', but we now know that this is not the only cause. Damaged axons can also be detected in areas that do not show signs of clear demyelination. Existing treatments have successfully reduced the number of relapses by targeting the immune component of the disease, but the neurodegenerative aspect remains an open target. This combined evidence suggested the existence of alternative mechanisms of axonal damage and we have recently identified at least two novel mechanisms of damage and are working towards the development of new treatments. One of the lead candidates is being tested in animal models of MS and the first results are spectacular and we hope to translate them into therapy for patients with severely impaired motor function.

Videos:
Mitochondrial Movement in Cortical Neurons
Mitotracker in Control Neurons
Mitotracker in Damaged Neuron
Mitotracker in Damaged Neuron Treated with MS-275
 
Casaccia Laboratory
Lab Location: Icahn 10-76
Office Location: Icahn 10-70F
Office: (212) 659-5988
Lab: (212) 659-5989
Lab Address:
Mount Sinai School of Medicine
1425 Madison Avenue, Room 10-76
New York, NY 10029

Admin Phone: (212) 659 - 5993
Admin Fax: (212) 849 - 2611

Mount Sinai School of Medicine
One Gustave L. Levy Place
Box 1065
New York, NY 10029

Courier Address:
Mount Sinai School of Medicine
1425 Madison Avenue, Room 9-23
New York, NY 10029
casaccia lab
epigenetics of neural repair