New Approach Helps Predict Neurodegenerative Diseases

Using the wobbler mouse as a model, the investigators focused on Vps54, which has a mutation that gives rise to progressive degeneration of motor neurons and to infertility.

Scientists discovered a domino effect in which reduced levels of the mutated protein have a destabilizing effect on the rest of the components of the GARP complex. "The illness develops not only because of the mutation but it may also be due to other mutations or defects that generate reduced levels of the GARP complex or instability therein," explained leader of the study Dr. Aitor Hierro at the Center for Cooperative Research in Biosciences (CIC bioGUNE; Bizkaia, Spain), a nonprofit biomedical research organization.

"The great similarity between the GARP complex proteins of the mouse and amongst humans means that such that a motorneurodegenerative effect in humans due to reduced levels of the GARP mooring complex cannot be discarded. This opens the possibility for studying these levels in humans where, moreover, it will be possible to predict the illness well before the appearance of symptoms," explained Dr Hierro. "It is highly likely that many patients with some motorneurodegenerative disease do not have the same mutation as the wobbler mouse but there does exist the possibility that due to some other reason, some patients may have reduced levels of the GARP complex, a situation which gives rise to the illness."

The GARP complex is the transport network that recycles receptors of acid hydrolases from the lysosomes to the Golgi apparatus. Acid hydrolases in the acidic medium of the lysosomes are activated and digest other proteins.

Subsequently vesicles fuse to discharge their transported content. To avoid the receptors themselves being digested by the acid hydrolases, once the interior of the lysosomes is acidified, these recycle to the Golgi by means of transport vesicles. In this way, the receptors are recycled and reused to transport new acid hydrolases to the lysosomes.

The study concluded that the wobbler phenotype is the consequence of a drastic reduction in the levels of the GARP complex, one that is required to tie up the transport vesicles to the Golgi apparatus. This drop in the levels of the GARP complex thus breaks with the normal functioning of the recycling route of the acid hydrolase receptors to the Golgi apparatus.

The study appeared in the August 14, 2010, edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS).

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