PiN Faculty Member - Mustafa Sahin, MD, PhD

Mustafa Sahin, MD, PhD

Associate Professor of Neurology

Boston Children's Hospital
F.M. Kirby Neurobiology Center
Center for Life Science, Room 14-073
3 Blackfan Circle
Boston, MA 02115
Tel: 617-919-6258
Fax: 617-730-0242
Email: mustafa.sahin@childrens.harvard.edu



The research in the Sahin lab is directed at understanding the cellular mechanism(s) of neuronal wiring and its relationship to neurological dysfunction. There are two major lines of ongoing research in the lab. First is the role of tuberous sclerosis genes TSC1 and TSC2 in neuronal wiring. Tuberous sclerosis complex (TSC) is a multi-system autosomal dominant disease, which is characterized by the formation of benign tumors (hamartomas) in several organs. The brain is almost invariable affected, and patients can present with epilepsy, autism and intellectual disability. However, a key, unresolved issue is what causes the neurological symptoms in TSC patients. Our lab has generated evidence that the miswiring of connections between neurons contributes to the pathogenesis of TSC using mouse models. The miswiring correlates with defects at the level of axonal specification, guidance and myelination. More recently, we have been investigating the role of TSC/mTOR signaling cascade in specific circuits in the CNS. We have generated a cerebellar Purkinje neuron-specific knockout of Tsc1 that displays autistic-like features, such as impairments in social interaction and repetitive behaviors. Importantly, treating these mice with an mTOR inhibitor prevents the development of these aberrant behaviors. These experiments support the notion that neurological defect in Tsc-deficient mice can be blocked by postnatal mTORC inhibition and have led to the design of clinical trials in patients with TSC, including one we are conducting at Boston Children’s Hospital.

The second major line of ongoing research is the role of axonopathy in spinal muscular atrophy (SMA). SMA is an autosomal recessive disease characterized by hypotonia and muscle weakness due to loss of the spinal motor neurons. Molecular genetic studies has revealed that mutations in SMN1 gene are responsible for this disease, and the SMN protein is involved in RNA processing. Despite these advances, little is known regarding the exact role of SMN in nervous system function, and the nature of the RNA processing defects that underlie SMA pathology have remained elusive. Recently, it was reported that SMN is localized to the axon and the growth cone. Furthermore, in the absence of full-length SMN, the axons are shorter, and the growth cones are smaller. Taken together, these findings suggest that dysregulation of RNA transport or translation may underlie SMA pathology. Currently, we are characterizing role of SMN gene in axon outgrowth and guidance in vivo and searching for the RNA cargos and translationally-regulated neuronal targets of SMN.

To study axonal development, the Sahin lab utilizes a variety of in vivo and in vitro assays and molecular and biochemical techniques. We use primary neuronal cultures as well as axon tracing experiments using fluorescently labeled tracers, and they take advantage of mouse models of neurological disease and generate neuronal cultures from these mice. In addition, we are employing biochemical analyses to quantitatively measure the relative abundance of proteins and RNA in isolated fractions and complexes. We are performing behavioral characterization of mouse models and using MRI and EEG in mice and in patients as potential translatable biomarkers. We are starting to use patient derived human neurons to model disease. Employing these varied techniques, we are investigating the regulation of neuronal wiring at the molecular, cellular and circuit levels.



Last Update: 5/12/2014



Publications

For a complete listing of publications click here.

 


 



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