Using an atypical research
model, the neuron, Patrick Delmas, of the "Intégration des
Informations Sensorielles Laboratory" (CNRS Marseille), and
the research teams of Dr. Jing Zhou(1) and Professor
David A. Brown(2) , have achieved significant results
with the function of polycystin-1, a human kidney protein whose mutations
have been associated with 85% of all cases of polycystic kidney disease.
Their work will enable the identification of the metabolic pathways activated
by polycystin-1 and provide valuable information about the cellular mechanisms
responsible for this disease. These results were published in the March
29 issue of the Journal of Biological Chemistry.
Autosomal dominant polycystic
kidney disease (called ADPKD) is a serious genetic disease with an incidence
rate of 1 per 1000 births, which afflicts about 80,000 people in France.
Fluid-filled cysts form in the kidneys of ADPKD patients and gradually
compress and destroy healthy renal tissue. The disease is one of the primary
causes of chronic kidney failure and almost half of all cases require
either dialysis or transplantation. The probability of end-stage kidney
failure requiring dialysis is 20-25% by the age of 50, 40% by the age
of 60, and between 50 and 70% by the age of 70. Treatment to slow the
progress of kidney failure in ADPKD patients has thus far been disappointing.
ADPKD is caused by the mutation of two genes, PKD1 and PKD2, respectively
located on autosomal chromosomes(3) 16 and 4. The first
gene, PKD1, is responsible for the synthesis of a glycoprotein called
polycystine-1 whose function is still poorly understood. This protein
is found in the tubular epithelia of the kidney and in the hepatic, biliary
and pancreatic canaliculi of polycystic kidneys. Mutations of the PKD1
gene lead to a dysfunction in the cellular differentiation of renal epithelium.
The second gene, PKD2, is responsible for the synthesis of a much smaller
protein, polycystin-2, which plays a role in calcium transport. PKD2 mutations
may have repercussions on fluid secretion and the growth of cysts.
The study of polycystin-1 has long been frustrated by the difficulty posed
by its expression(4) in conventional cells lines due
to its large size. To enable the expression of this protein, the researchers
cultured sympathetic neurons(5) from rats. Polycystin-1
genes of different species (humans and mice) were introduced inside the
nucleus of the neurons using an intranuclear microinjection technique.
This method proved very effective for studying polycystin-1 functions.
The work of Patrick Delmas and his associates demonstrated that polycystin-1
behaves like a membrane receptor that couples with G-proteins(6)
, activating them in an unpredictable manner.
With this work, the researchers are among the first to propose a function
for polycystin-1 and suggest a molecular explanation for the development
of polycystic kidney disease: G-proteins regulate a variety of enzymes
such as adenylate cyclase and protein kinases. These enzymes are known
to play a key role in controlling the secretion of fluids, cell proliferation,
and differentiation, three basic functions that are severely disrupted
Researchers suggested that the mutations of polycystin-1 affect its integrity,
thus activating pathogenic responses through the abnormal stimulation
of G-proteins. The identification of the functions of polycystin-1 may
well pave the way toward developing new therapeutic strategies for treating
polycystic kidney disease.
Delmas P., et al.. Constitutive activation of G-proteins by polycystin-1
is antagonized by polycystin-2, Journal of Biological Chemistry,
March 29, 2002.
Division, Harvard Medical School, Boston
(2)Wellcome Laboratory for Molecular Pharmacology, UCL,
(3)Autosomes are non sex-determining chromosomes. In humans,
there are 23 pairs of chromosomes of which 22 are autosomal. The 23rd
pair are the sex-determining chromosomes X and Y (heterosomes).
(4)Method employed to introduce a minigene inside the
host cell to study its functions
cervical ganglia neurons that were part of the autonomous nervous system
and maintained in primary culture
(6)Coupling proteins associated with membrane receptors
provide signal transduction from the extracellular medium to the intracellular
medium and regulate cellular metabolism
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