Johns Hopkins School of Medicine

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 few 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

To understand both normal motor neuron and peripheral nerve biology and pathological events that cause neurodegeneration, we aim to identify the genetic causes of SMAs and CMTs in families with novel phenotypes.  To date, we have identified mutations in the genes encoding the p150Glued subunit of dynactin (a microtubule motor protein important for retrograde motor axonal transport), Fbox38 (a transcription factor), transient receptor vanilloid 4 (TRPV4-a cation channel), and JAG1 (a Notch ligand).  Because TRPV4 is a surface expressed ion channel, it represents an attractive target for therapeutics. We have demonstrated that TRPV4 mutations cause a gain of channel function and increased intracellular calcium concentrations.  We are currently studying cellular, drosophila, and mouse models of this disorder in order to characterize the normal and pathological roles of TRPV4 in the nervous system in vivo and investigate whether TRPV4 small molecule antagonists can mitigate disease.

Investigating the molecular and cellular mechanisms of proximal SMA

The autosomal recessive motor neuron disease proximal SMA is 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 impairments of motor axon radial growth and sorting as well as neuromuscular junction synaptic dysfunction starting prenatally in SMA mouse models and human tissues followed by rapid neurodegeneration that occurs neonatally.  Studies are ongoing to dissect the molecular basis of this developmental failure and determine 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 tissues collected during expedited autopsies. 

Developing therapies for SMAs

Recent success in therapeutic development for SMA has led to FDA approvals of AAV9 mediated gene replacement therapy and splice switching antisense oligonucleotides. It is anticipated that approval of orally bioavailable splice switching small molecules is soon to follow. These advances represent a breakthrough for neurodegenerative disease, but efficacy remains variable in patients. Ongoing studies are focused on defining why activity of currently delivered drugs is not optimal in all patients, characterizing novel therapeutic targets that can be used in combination with current drugs, and developing molecular biomarkers of disease. In one ongoing project, we have defined a novel lncRNA that regulates SMN expression during development and are developing ASOs to target this RNA in combination with splice switching ASOs.