Genes 2 Brains 2 Mind 2 Me

Commuting to work is a total drag.  Commuting to work in New York City is not just a total drag, but THE definitive commuting nightmare.  Still, when one ponders the masses of people (more than 2 million each day) who tread in, out and around Manhattan, its pretty remarkable that one can get in to work and home again.

Consider then, the human brain, with 100 billion neuons and 1,000 trillion synapses – all of which need constant tender loving care and maintenance to keep firing along.  In some cases, the commute to these synapses can be quite long – even for a molecule (eg. if a motor neuron were as wide as my car, the commute from the nucleus to the presynaptic membrane would be about 10 miles, which is about how long I must travel to get to work).  Is the brain better able to transport cargo from home (the nucleus where lots of the basic materials are produced) to work (synaptic membranes which carry out information transfer) ?

I certainly hope so.  But, like my own commute, it seems the human brain can have commuting nightmares of its own.  One of the main transport vehicles in the brain is a molecule called Kinesin which literally walks (see the movie below) along microtubule tracks and delivers its cargo in little molecular satchels called protein transport vessicles.  One of the components of these transport vessicles, a protein known as piccolo,  is expressed in presynaptic zones and may be important for recycling presynaptic vessicles – as well as mental health.

Indeed, what might happen if the normal process of vessicle transport and synaptic maintenance were disrupted in the brain – a commuting debacle of sorts ? Well, Sullivan and colleagues [doi: 10.1038/mp.2008.125] report that a genome-wide association study of major depressive disorder yields piccolo (PCLO) as one of its major findings.  The single nucleotide polymorphism rs2522833, which encodes a serine to alanine substitution near the calcium binding region (amino acid #4814) of PCLO was one of the most significant findings in the original study and a follow-up of a different case/control population study on major depressive disorder. The change from alanine to serine is notable, since the addition of N-acetylglucosamine to serine residues is a common mechanism for regulating intracellular traffic.

My 23andMe profile shows an AA for this site, which is the serine/serine form of PCLO (the form which can be modified by GlcNA  -yay!) rather than the alanine/alanine form. This (A) allele is indicated as the major allele by the authors although the AA genotype is less common among individuals of European and Asian ethnicity, but quite common in sub-Saharan Africa.  The authors don’t reveal which allele is associated with an increased risk of depression, but I already know the answer – I’ll never recover from the depression of my own commuting nightmare.

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