BSCB Science Writing Prize 2009

Shaping the proteins that cause blindness | Back

By John Bett, Division of Molecular & Cellular Neuroscience, UCL Institute of Ophthalmology, London.

The ability to see the world around us is integral to so much that makes us human.  The appreciation of literature and art or looking into the eyes of a loved one or friend are among the most uplifting experiences. Indeed, the English essayist Joseph Addison claimed our sight is the most important of all our senses, arguing that “it fills the mind with the largest variety of ideas and continues the longest in action without being tired or satiated”.  While the visual process has fascinated philosophers and scientists from Plato to Newton, the current tools at scientists’ disposal has given us a deep understanding of the involvement of genes and their protein products in healthy vision and blindness. 

In order to carry out their normal cellular role, all proteins must undergo a process called “folding”, whereby they form a complex three-dimensional shape.  It is only through forming their unique shape that they are able to undertake their individual cellular responsibilities.  When proteins fail to form their native shape due to a mutation in their genetic code, they become unable to carry out their cellular functions and can lead to a variety of human disease.  Certain forms of inherited blindness are now known to belong to this class of genetic disease. Understanding how proteins fail to adopt their correct shape in these types of blindness is an important challenge to cell biologists, and it is through basic research into such diseases that biomedicine will realise its potential to develop therapeutics for such visual maladies.   

Before we can appreciate the importance of protein folding in the visual system however, we must first consider vision itself.  Vision is the remarkable ability of our eyes and brains to detect and decode a tiny proportion of the electromagnetic spectrum known as visible light.  The fact that life on Earth has evolved to utilise such cosmic information is nothing short of miraculous, and underlines the immense advantage of sight to survival on our planet.  So how do we actually sense light?  Our retinas are loaded with two classes of sensory neuron - rod and cone photoreceptors - which together detect the entire range of wavelengths of the visible spectrum.  This detection is mediated through specialised light-absorbing proteins called opsins, which are densely stacked at the tips of the photoreceptors, awaiting photon arrival.  Light information is then converted into nerve impulses and sent to the visual cortex for processing to create the image we see in our mind’s eye.

For most of us, this process is something we will hitherto have had little reason to consider.  For the bench scientist however, probing the inner workings of protein folding in photoreceptors is proving extremely fascinating.  Neurons are known to be particularly vulnerable to toxicity caused by misfolded proteins, as exemplified by degenerative disorders such as Huntington’s or Parkinson’s disease.  For photoreceptor neurons the problem is arguably more severe, due to their fastidious demands for the production of massive amounts of specialised proteins needed for light detection.

Enter the molecular chaperone.  Like all cells, photoreceptors come equipped with their own arsenal of the aptly named molecular chaperones to assist in the correct folding of important cellular proteins.  Such molecular chaperones, named for their ability to prevent promiscuous protein interactions, are vital to maintaining a healthy cellular environment.  If these natural cellular defence barriers are overloaded with mutant proteins, proteins which adopt the wrong shape can disturb the function of other essential proteins.  The result of this is a cellular catastrophe which ultimately will lead to dysfunction and death of the cell.

Take the most common inherited blindness, retinitis pigmentosa (RP).  This set of retinal diseases begins with night blindness, proceeding gradually towards tunnel vision and in many cases total blindness.  Of the many mutant genes which cause RP, particular mutations in the gene for rhodopsin – the light-sensitive protein in rod photoreceptors – are among the most intriguing.  A defining characteristic of one such mutation (P23H) is the misfolding and cellular accumulation of the faulty protein.  Cell biologists can mimic this process by tricking human cell lines into producing the variant protein and studying how it accumulates into large cellular deposits (see image).  The production of such high-volume cellular junk appears to place such a stress on photoreceptors that the molecular chaperone machinery is overcome.  This ultimately causes the cells to die, resulting in a gradual loss of sight.

Another, more severe form of inherited blindness is Leber Congenital Amaurosis (LCA).  Children born with this devastating disease become fully blind within a few months of birth.  Mutations in a special retinal molecular chaperone called AIPL1 are known to lead to this condition, underscoring the importance of protein folding to normal vision.  It is thought that the AIPL1 retinal chaperone interacts with other molecular chaperones to ensure the correct folding of essential retinal enzymes, a theory that is currently being investigated using cell models to study such protein interactions.  In the case of LCA when AIPL1 is non-functional, the proteins required to transmit the light signal to the brain are no longer assembled correctly, leading to complete blindness.  Defining the exact proteins that AIPL1 helps to fold remains one of the most exciting challenges in the study of this particular form of blindness.

So just by scratching the surface of the visual system and looking at these two inherited diseases can we see the huge importance of cellular protein folding to normal vision.  And now the challenge for biomedical researchers is to harness basic research into developing potential therapies for human disease.  In the case of inherited blindness caused by defects in protein folding, it is possible that drugs which improve protein folding or enhance the disposal of toxic misfolded proteins may offer therapeutic benefit.  However, it should be noted that not all basic research is aimed at finding a druggable target.  But it should not matter.  As the great Scottish bacteriologist Sir Alexander Fleming remarked, “One sometimes finds what one is not looking for”.