Scientists identified several molecules capable of reversing the
brain abnormalities of
Parkinson's disease (PD), while also uncovering new clues for its origin in a study just published in the journal
Disease Models and Mechanisms. PD is characterised by abnormal deposits of a brain protein called alpha-synuclein throughout the damaged brain regions, but exactly what they do there is not clear. The fact that their numbers and spreading are associated disease progression has made them, however, a major point of interest in PD research. The work now published suggests that these deposits are actually a normal physiological process to purge unwanted proteins but, when "overloaded", they can also cause of the cellular abnormalities seen in PD neurons and, ultimately, neural death. This would explain why the disease tends to appear later in life when the whole
metabolism (including this mechanism) becomes less efficient, and also why neurons are particularly susceptible as they are one of the few cells of the body that are not replaced when old and less capable. The study uses a yeast model of PD showing once again the power of simple organism models in the understanding of extremely complex human diseases.
PD is neurodegenerative disease characterised by increasing motor problems - tremors, rigidity and balance and coordination problems - that can leave the patient incapable of perform the simplest of everyday task. Many patients also suffer from non-motor symptoms, including dementia. There is also widespread death of dopamine-producing (dopaminergic) neurons in a part of the brain called the substantia nigra. Since dopamine acts as messenger between this region (the control centre) and other neurons around the body to ensure proper regulation of the body's movement, these deaths are believed to cause PD motor disability.
Although the symptoms can be treated with dopamine replacement therapies, as the disease progresses, they stop working and, more importantly, PD is, ultimately, incurable. With the spread of the disease throughout an increasing aging human population bringing dramatic financial and social costs (who will take care of these millions of patients?), new treatments and/or a cure are now being exhaustively researched.
A major focus of the research has been a brain protein of unknown function called alpha-synuclein. In fact, deposits of abnormally folded alpha-synuclein (a certain folding is associated to the proper functioning of each protein) are found in inclusions dispersed all over the damaged brain areas of PD patients. The role of these inclusions in disease is not known with hypotheses ranging from having no importance, to contribute to neural death or even serve to avoid death by rendering harmless toxic misfolded proteins. What is known, however, is that these alpha-synuclein inclusions are excellent markers of disease progression - they accompany the brain degeneration.
In 2003 Tiago Outeiro - a Portuguese scientist and one of the first authors of the new study - and Susan Lindquist - the team leader in both studies - created a yeast model of PD by inserting the alpha-synuclein gene in yeast, an organism that normally does not have the protein. Remarkably, this created in yeast some of the cellular abnormalities seen in PD affected neurons. And as alpha-synuclein quantities increased, also the numbers of inclusions containing the protein, in such a way that led the researchers to suggest that these were, in fact, a physiological process for getting rid of unwanted proteins. And that maybe PD appeared when the capacity of the system was exceed. This hypothesis was supported by the fact that multiplications of the normal alpha-synuclein gene (leading to protein overproduction) were known to cause some forms of human PD, and also by the disease tendency for a late onset, probably due to an aging and less metabolically capable body.
To test this possibility in the study now published, Linhui Julie Su, Pavan K. Auluck, Tiago Fleming Outeiro and Susan Lindquist, working at the Whitehead Institute for Biomedical Research, Cambridge USA, created yet another yeast PD model this time with even higher levels of alpha-synuclein (High-syn) by inserting extra copies of the gene in the yeast genome. This PD model was then compared with yeast producing none or intermediate levels of alpha-synuclein (Int-syn) (this last organism was the one used in the 2003 study)
Remarkably, the new High-syn yeast suffered from several more of the cellular abnormalities characteristic of PD than the Int-syn yeast. The new abnormalities included problems with mitochondria (the energy producing factories of the cell) as well as accumulation of toxic free radicals, in addition to the abnormalities in lipid transport mechanisms already detected in Int-syn yeast. Problems in mitochondria and accumulation of free radicals are particularly interesting as, although seen in many PD patients, until now they had been impossible to link to alpha-synuclein.