Thousands of patients submitted to DNA analysis and outcome published in  Nature Genetics

Within the context of an international research project, researchers analyzed the genome (genetic make-up) of more than  2000 patients suffering from a severe and rare form of parkinsonism, called Progressive Supranuclear Palsy (PSP).  The results were compared with those obtained in 7000 control subjects without the disease.  The analysis was carried out in two phases, starting from an initial sample of 1114 subjects who had died, in whom the diagnosis was certain, based on the outcome of their autopsy.

There were also unexpected results. Variants connected to the risk of developing PSP  were located in three genes that code proteins involved in particular mechanisms inside nervous cells

PERK (EIF2AK3), a factor that is activated when the endoplasmic reticulum (which may be considered the storehouse of the cell) is overflowing with proteins; it blocks the building of more proteins so that the endoplasmic reticulum has time to dispose of the proteins that it has accumulated.   It is well known that misfolded proteins occur and tend to accumulate in parkinsonisms and that this phenomenon is particularly common in the dopaminergic neurons of the substantia nigra.

Sintaxin (STX6)  belongs to the class of proteins that contribute to the transport mechanisms  within vesicles in the cell.   They could influence the transport of misfolded proteins to lysosomes, which are small organs responsible for the grinding and elimination of old compounds (”trash”) that do not work, such as misfolded proteins

MOBP, a fundamental protein for myelin, a white sheath that covers the axon of nerves in the white substance.  It is well known that in PSP the white substance is damaged in many cerebral areas.

The demonstration of the involvement of the gene responsible for the production of PERK is of particular interest, as it suggests that the activation of a response to the accumulation of misfolded proteins occurs not only as a consequence of the neurodegenerative process, but actually is part of the process itself.  Therefore, this mechanism could be used as a target to develop innovative treatment  for parkinsonisms.

Source: Hoglinger GU and coll. Nature Genetics 19th June 2011 online