Research summary

tRNA Synthetases and Neurodegeneration

The process of deciphering the genetic code to produce protein requires aminoacyl-tRNA (aa-tRNA) which are specific tRNA ligated to their specific amino acid.  Each aa-tRNA recognizes their target mRNA codon and allows the correct amno acid to be incorporated into a growing polypeptide chain. An ancient and ubiquitous group of enzymes, the aminoacyl tRNA synthetases (ARS) perform the key task of ligating tRNA with their cognate amino acid. It is therefore surprising that mutations in ARS such as glycl-tRNA synthetase or tyrosyl-tRNA synthetase can lead to the peripheral nerve disorders distal spinal muscular atrophy and Charcot-Mare-Tooth. Understanding why neurons are selectively vulnerable to defects in a critical housekeeping gene will be broadly applicable to a range of common disabling neurodegenerative conditions

The Neurobiology of Migraine

The other major area of research for the group is understanding pathogenic mechanism in migraine. Migraine is a common, costly and debilitating condition with a complex genetic aetiology. The genetics basis of typical migraine is mostly unknown but we have identified the first gene underlying typical migraine. We found in a large family with migraine, a frameshift mutation in the gene KCNK18, which encodes a tandem-pore background potassium channel, TRESK. TRESK is highly expressed in dorsal root, trigeminal and autonomic ganglia and to lesser extents in the brain and spinal cord. In vitro electrophysiology demonstrates the mutation, which produces a prematurely truncated protein, causing complete loss of function when expressed alone and a dominant negative effect when expressed with wildtype channels. We believe that loss of TRESK function increases cell excitability and responsiveness and thereby lowers the threshold for migraine development. We are building on these findings to further our understanding of migraine and develop new drug treatments.

Zam Cader studied Medicine at the University of Birmingham (1991-97) and continued his general medical training in Oxford. He then spent three years, working on the genetic linkage and association of  neurological disorders unnder the supervision of Professor George Ebers at the Wellcome Trust Centre for Human Genetics. After obtaining his DPhil in 2003, he completed his training in Clinical Neurology at Oxford. He is now an Honorary Consultant Neurologist at the John Radcliffe Hospital with an interest in Neurodegenerative Disorders. He joined the Department of Physiology, Anatomy and Genetics in 2007 after being awarded an MRC Clinician Scientist Fellowship to establish his own research group.

Collaborators

• Gregory Weir, DPhil Student
• David Lau, MSc Student
• Jinghuan Li, Post Doc Researcher
• Stuart Grice, Post Doc Researcher
• Kevin Talbot
• Ji-Long Liu
• Holly Bridge
• Colin Akerman