Charlotte Sumner MD
Associate Professor of Neurology and Neurosciencecsumner1@jhmi.edu
Telephone Number: 410-614-0093
Fax Number: 410-502-5459
School of Medicine
855 North Wolfe Street
Baltimore MD, 21231
Genetic and cellular mechanisms of motor neuron disease
The goal of our laboratory is to determine the genetic and molecular mechanisms of neurodegenerative disorders of motor neurons and peripheral nerves. Spinal muscular atrophies (SMAs) and various forms of Charcot-Marie-Tooth disease (CMT) are among the most common inherited neurological disorders and cause progressive weakness of muscle, sensory loss, and often, early mortality. Currently, there are no disease-modifying therapies to offer patients. Our research aims are: 1) to genetically characterize these diseases, 2) to investigate molecular and cellular mechanisms of disease pathogenesis, and 3) to develop novel therapeutic strategies. Some of our ongoing research projects are:
Identifying novel genetic causes of SMAs and CMTs In order to further understand both normal motor neuron and peripheral nerve biology and pathological events that cause neuronal degeneration, we aim to identify the genetic causes of SMAs and CMTs in families with novel phenotypes. We have previously identified mutations in the p150Glued subunit of dynactin, a microtubule motor protein important for retrograde motor axonal transport, as the cause of a novel form of SMA characterized by vocal fold and hand weakness. We have also identified mutations in the transient receptor vanilloid 4 gene (TRPV4) in patients with CMT2C and scapuloperoneal SMA. TRPV4 encodes a cation channel and the disease-associated mutations cause a gain of channel function, increased calcium influx, and neuronal toxicity in vitro. We are currently studying cellular, drosophila, and mouse models of this disorder in order to further investigate the normal and pathological roles of TRPV4 in motor and sensory neurons in vivo.
Investigating the molecular and cellular mechanisms of SMAs A major focus of our work is the autosomal recessive motor neuron disease proximal SMA, the most common inherited cause of infant mortality. SMA is caused by mutation of the survival motor neuron 1 (SMN1) gene, retention of the SMN2 gene, and deficiency of the SMN protein. The SMN protein plays an essential role in synthesizing small nuclear ribonuclear proteins (snRNPs), which are critical components of the spliceosome. In order to understand how SMN protein deficiency causes motor neuron dysfunction and degeneration, we study the molecular, cellular, and physiological events during disease pathogenesis in SMA mice and human tissues. We have identified specific abnormalities of neuromuscular junction (NMJ) synapse as well as of excitatory synaptic inputs to motor neurons in the spinal cord. Studies are ongoing to further characterize particular synaptic components altered by SMN protein deficiency and to establish whether this is a cell autonomous process. In order to establish the relevance of these observations to the human disease, we have established a tissue bank of SMA and age-matched normal control autopsy specimens.
Developing therapies for SMAs All patients with proximal SMA retain one or more copies of the SMN2 gene. When this gene is expressed at sufficient levels, it can prevent SMA disease manifestations. Thus a principal goal of our therapeutics development efforts is to identify small molecules that activate SMN2 expression. We have shown that histone decetylase (HDAC) inhibitors can increase SMN levels in vitro and in vivo and significantly ameliorate the disease phenotype in SMA mice. We are currently evaluating novel SMN inducing compounds that are being developed for the treatment of SMA patients.