The source of this article is Scientific American: http://tinyurl.com/7mube

June 27, 2005

New Movement in Parkinson's

Recent genetic and cellular discoveries are among the advances pointing to 
improved treatments for this increasingly common disorder

By Andres M. Lozano and Suneil K. Kalia

Parkinson's disease, first described in the early 1800s by British 
physician James Parkinson as "shaking palsy," is among the most prevalent 
neurological disorders. According to the United Nations, at least four 
million people worldwide have it; in North America, estimates run from 
500,000 to one million, with about 50,000 diagnosed every year. These 
figures are expected to double by 2040 as the world's elderly population 
grows; indeed, Parkinson's and other neurodegenerative illnesses common in 
the elderly (such as Alzheimer's and amyotrophic lateral sclerosis) are on 
their way to overtaking cancer as a leading cause of death. But the disease 
is not entirely one of the aged: 50 percent of patients acquire it after 
age 60; the other half are affected before then. Furthermore, better 
diagnosis has made experts increasingly aware that the disorder can attack 
those younger than 40.
So far researchers and clinicians have found no way to slow, stop or 
prevent Parkinson's. Although treatments do exist--including drugs and 
deep-brain stimulation--these therapies alleviate symptoms, not causes. In 
recent years, however, several promising developments have occurred. In 
particular, investigators who study the role proteins play have linked 
miscreant proteins to genetic underpinnings of the disease. Such findings 
are feeding optimism that fresh angles of attack can be identified.

As its 19th-century name suggests--and as many people know from the 
educational efforts of prominent Parkinson's sufferers such as Janet Reno, 
Muhammad Ali and Michael J. Fox--the disease is characterized by movement 
disorders. Tremor in the hands, arms and elsewhere, limb rigidity, slowness 
of movement, and impaired balance and coordination are among the disease's 
hallmarks. In addition, some patients have trouble walking, talking, 
sleeping, urinating and performing sexually.



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Perhaps one day CHAPERONE-TYPE DRUGS can be developed to limit degeneration 
in people.
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These impairments result from neurons dying. Although the victim cells are 
many and found throughout the brain, those producing the neurotransmitter 
dopamine in a region called the substantia nigra are particularly hard-hit. 
These dopaminergic nerve cells are key components of the basal ganglia, a 
complex circuit deep within the brain that fine-tunes and coordinates 
movement. Initially the brain can function normally as it loses 
dopaminergic neurons in the substantia nigra, even though it cannot replace 
the dead cells. But when half or more of these specialized cells disappear, 
the brain can no longer cover for them. The deficit then produces the same 
effect that losing air traffic control does at a major airport. Delays, 
false starts, cancellations and, ultimately, chaos pervade as parts of the 
brain involved in motor control--the thalamus, basal ganglia and cerebral 
cortex--no longer function as an integrated and orchestrated unit.

Proteins Behaving Badly
In many Parkinson's cases, the damage can be seen in autopsies as clumps of 
proteins within the substantia nigra's dopaminergic neurons. Such protein 
masses also feature in Alzheimer's and Huntington's--but in Parkinson's 
they are called Lewy bodies, after the German pathologist who first 
observed them in 1912. Like researchers studying those other 
neurodegenerative diseases, Parkinson's investigators heatedly debate 
whether the protein clusters themselves cause destruction or are protective 
and endeavoring to remove toxic molecules from the neurons. Regardless of 
their position, however, most agree that understanding these accumulations 
is key to understanding Parkinson's.

Two cellular processes occupy a central place in this emerging story: 
protein folding and protein elimination. Cells synthesize proteins, which 
are chains of amino acids, based on instructions written in the DNA of 
genes. As the proteins are produced, molecules called chaperones fold them 
into the three-dimensional form they are supposed to take. These chaperones 
also refold proteins that have become unfolded.

If the chaperone system fails for some reason, proteins not properly folded 
in the first place or those that did not correctly refold become targeted 
for disposal by what is called the ubiquitin-proteasome system. First, 
ubiquitin, a small protein, is attached to a misshapen protein in a process 
called ubiquitinylation. Such tagging is repeated until ubiquitin chains of 
varying lengths end up draped over the ill-fated protein. These chains 
become the kiss of death. They alert the nerve cell's proteasome, a garbage 
disposal system, to the existence of the bedecked protein. The proteasome 
then digests it into its constituent amino acids. Aaron Ciechanover and 
Avram Hershko of Technion-Israel Institute of Technology and Irwin Rose of 
the University of California at Irvine were awarded the 2004 Nobel Prize in 
Chemistry for their work describing this system.

In the past few years, many scientists have come to believe that 
Parkinson's emerges when the chaperone and ubiquitin-proteasome systems 
malfunction. They reason that the disease process might go something like 
this: some form of injury to neurons of the substantia nigra triggers a 
cascade of cellular stresses [see "Understanding Parkinson's Disease," by 
Moussa B. H. Youdim and Peter Riederer; Scientific American, January 1997]. 
These stresses result in a wealth of misfolded proteins that congregate. 
This buildup might initially be protective because all the renegade 
proteins are herded together and thus prevented from causing trouble 
elsewhere in a cell. Chaperones then set to work refolding, and the 
disposal system starts eliminating those proteins that cannot be reformed. 
When the production of poorly folded proteins overwhelms the cell's ability 
to process them, however, trouble arises: The ubiquitin-proteasome system 
becomes inhibited, chaperones get depleted, and toxic proteins accumulate. 
Neuronal cell death follows.

Researchers espousing this hypothesis think it could explain Parkinson's 
two forms. An estimated 95 percent of patients suffer from sporadic 
disease--the results of a complex interplay between genes and the 
environment. When someone with a susceptible genetic background encounters 
certain environmental factors, such as pesticides or other chemicals, the 
cells in that individual's substantia nigra suffer more stress and 
accumulate more misfolded proteins than do the same cells in other people. 
In the remaining 5 percent of patients, Parkinson's appears to be 
controlled almost entirely by genetics. Discoveries in the past eight years 
have revealed a connection between mutations and either the buildup of 
misshapen proteins or the failure of the cell's protective machinery. These 
genetic insights have been the most exciting developments in the field in 
years.

The Genetic Frontier
At the National Institutes of Health in 1997, Mihael H. Polymeropoulos and 
his colleagues identified a mutation in a gene for a protein called 
alpha-synuclein in Italian and Greek families with an inherited form of 
Parkinson's. It is an autosomal dominant mutation, meaning just one copy 
(from the mother or the father) can trigger the disease. Mutations in the 
alpha-synuclein gene are extremely rare and insignificant in the worldwide 
burden of Parkinson's (they account for far less than 1 percent of 
patients), but identification of the link between the encoded protein and 
Parkinson's set off an explosion of activity--in part because 
alpha-synuclein, normal or otherwise, was soon found to be one of the 
proteins that accumulates in the protein clumps. Investigators reasoned 
that a better understanding of how the mutation leads to Parkinson's could 
suggest clues to the mechanism underlying Lewy body formation in 
dopamine-producing cells of the substantia nigra in patients with sporadic 
disease.

The alpha-synuclein gene codes for a very small protein, only 144 amino 
acids long, which is thought to play a role in signaling between neurons. 
Mutations result in tiny changes in the amino acid sequence of the 
protein--in fact, several such mutations are now known, and two of them 
result in the change of a single amino acid in the sequence. Studies of 
fruit flies, nematodes (roundworms) and mice have shown that if mutated 
alpha-synuclein is produced in high amounts, it causes the degeneration of 
dopaminergic neurons and motor deficits. Other studies have revealed that 
mutated alpha-synuclein does not fold correctly and accumulates within Lewy 
bodies. Altered alpha-synuclein also inhibits the ubiquitin-proteasome 
system and resists proteasome degradation. In addition, it has recently 
become clear that having extra copies of the normal alpha-synuclein gene 
can cause Parkinson's.


In 1998, one year after the discovery of the alpha-synuclein mutation, 
Yoshikuni Mizuno of Juntendo University and Nobuyoshi Shimizu of Keio 
University, both in Japan, identified a second gene, parkin, that is 
mutated in another familial form of Parkinson's. This mutation appears most 
often in individuals diagnosed before age 40; the younger the age of onset, 
the more likely the disease is caused by a parkin mutation. Although people 
who inherit a defective copy from both parents (that is, when the mutation 
is autosomal recessive) inevitably develop the disease, those who carry a 
single copy of the mutated gene are also at greater risk. Parkin mutations 
appear to be more common than alpha-synuclein gene mutations, but no good 
figure on incidence is currently available.

The parkin protein contains a number of amino acid sequences, or domains, 
common to many proteins. Of particular interest are two so-called RING 
domains; proteins with these RING domains are involved in the protein 
degradation pathway. Findings now suggest that neuronal death in this form 
of Parkinson's stems in part from the failure of the ubiquitinylation 
component of the protein disposal system: parkin attaches ubiquitin to 
misfolded proteins--without it, there is no tagging and no disposal. Our 
own work has recently shown that a protein called BAG5, which is found in 
Lewy bodies, can bind to parkin to inhibit its function and cause the death 
of dopamine-producing neurons.

Interestingly, some patients with parkin mutations lack Lewy bodies in 
their nigral neurons. This observation suggests that proteins may not form 
aggregates unless the ubiquitinylation process is functioning. It also 
suggests that when harmful proteins are not huddled together within Lewy 
bodies they create cellular havoc. Because patients with parkin mutations 
develop the disease early in life, it seems likely that they miss some 
initial protection conferred by having toxic proteins quarantined in clumps.

Several other recent discoveries highlight further genetically induced 
muck-ups in the cellular machinery. In 2002 Vincenzo Bonifati and his 
colleagues at Erasmus Medical Center in Rotterdam identified a mutation in 
a gene called DJ-1. Like that in parkin, this mutation is responsible for 
an autosomal recessive form of Parkinson's and has been found in Dutch and 
Italian families. Investigators have seen mutations in another gene, UCHL1, 
in patients with familial Parkinson's. A paper in Science just described a 
mutation in PINK1 that may lead to metabolic failure and cell death in the 
substantia nigra. And other work has identified a gene called LRRK2, which 
encodes the protein dardarin (meaning "tremor" in the Basque region, where 
the affected patients came from). It, too, is involved with metabolism and 
appears in familial Parkinson's. But researchers are not far along in 
understanding exactly what all these mutations set wrong.

New Avenues for Treatment
Because the insights just described involve molecules whose activity could 
potentially be altered or mimicked by drugs in ways that would limit cell 
death, the discoveries could lead to therapies that would do more than ease 
symptoms--they would actually limit the neuronal degeneration responsible 
for disease progression.

This strategy has yielded two intriguing results. Increasing the levels of 
chaperones in cells of the substantia nigra has been found to protect 
against the neurodegeneration set in motion by mutated alpha-synuclein in 
animals. Recent studies using fruit-fly models of Parkinson's have shown 
that drugs that induce chaperone activity can offer protection against 
neurotoxicity. Perhaps one day chaperone-type drugs can be developed to 
limit degeneration in people, or gene therapy could be devised to trigger 
the production of needed chaperones. In addition, investigators have found 
that increasing the amount of normal parkin protein in cells protects 
against the neurodegeneration resulting from noxious, misfolded proteins. 
Much more study will be needed, however, to determine whether such 
interventions could be made to work in humans.


In addition to pursuing the preliminary leads that have arisen out of the 
new protein-related and genetic findings, investigators have begun 
introducing neurotrophic factors--compounds promoting neuronal growth and 
differentiation--into the brain. These agents not only alleviate symptoms 
but also promise to protect neurons from damage or even to restore those 
already harmed.

One line of research in animals, for instance, suggests that a family of 
proteins called glial cell line-derived neurotrophic factor (GDNF) can 
enhance the survival of injured dopamine neurons and dramatically reduce 
parkinsonian symptoms. Steve Gill and his colleagues at Frenchay Hospital 
in Bristol, England, have embarked on a pilot study to give Parkinson's 
patients GDNF. Surgeons insert a catheter into the left and right striatum, 
the main recipients in the basal ganglia of the dopamine secreted by 
neurons of the substantia nigra. Minute volumes of GDNF are then 
continuously infused to the brain from a pump set into the abdomen. The 
pump holds enough GDNF to last one month and is replenished during an 
office visit; a syringe pierces the skin and refills the pump reservoir.

Initial results in a handful of patients suggested that symptoms had 
improved, and PET scans indicated some restoration in dopamine uptake in 
the striatum and substantia nigra. But the results of a larger, more recent 
trial have been unconvincing: patients who received saline solution fared 
no better than those who received GDNF. Nevertheless, many of us who work 
in this area feel that this approach is still worth pursuing. It is not 
unusual in medicine for the first forays into a treatment to be negative. 
Levo-do-pa, for instance, initially showed no benefit and only unwanted 
side effects; now it is one of the principal treatments for Parkinson's.

Other researchers are using gene therapy instead of surgery to administer 
GDNF, hoping the delivered gene will provide a long-term supply of this 
neurotrophic agent. Jeffrey H. Kordower of Rush Presbyterian-St. Luke's 
Medical Center in Chicago and Patrick Aebischer of the Neurosciences 
Institute at the Swiss Federal Institute of Technology and their colleagues 
engineered a lentivirus to carry the gene for GDNF and deliver it to 
dopamine-producing striatal cells in four parkinsonian monkeys. The results 
were impressive: the monkeys' motor problems significantly diminished, and 
they were unaffected by a subsequent injection of MPTP, a chemical toxic to 
dopamine neurons of the substantia nigra. The introduced gene induced cells 
to make the protein for up to six months, after which the experiments were 
stopped. Based on these studies, scientists at Ceregene in San Diego are 
using a similar technique to deliver the protein neurturin, a member of the 
GDNF family. Although the studies are in the preclinical phase, researchers 
plan to test a gene similar to the gene for neurturin in human patients.

Still other forms of therapy are being investigated. Working with Avigen 
near San Francisco, Krys Bankiewicz has shown in animals that placing the 
gene for an enzyme called aromatic amino acid decarboxylase in the striatum 
can enhance dopamine production in this area of the brain. In rats and 
monkeys this approach has also ameliorated parkinsonian symptoms. Trials in 
patients have been approved and will be launched soon.

Michael Kaplitt of Cornell University and his team are taking a different 
tack, using gene therapy to shut down some of the brain regions that become 
overactive when dopamine released from the substantia nigra falls too 
low--including the subthalamic nucleus of the basal ganglia. (The loss of 
dopamine causes neurons making glutamate, an excitatory neurotransmitter, 
to act unopposed and thus overstimulate their targets, causing movement 
disorders.) Kaplitt will begin human trials using a virus to introduce the 
gene for glutamic acid decarboxylase--which is crucial to the production of 
the inhibitory neurotransmitter gamma amino butyric acid (GABA)--to these 
sites. He and his co-workers hope that the GABA will quell the overexcited 
cells and thus calm parkinsonian movement disorders. In the experiments, 
they thread a tube about the width of a hair through a hole the size of a 
quarter on top of a patient's skull. The tube delivers a dose of virus, 
which ferries copies of the gene into neurons of the subthalamic nucleus. 
The chemical released from the altered cells should not only quiet the 
overactive neurons residing in that region but may be dispatched to other 
overactive brain areas.


Perhaps the most hotly debated potential treatment entails transplanting 
cells to replace those that have died. The idea has been to implant 
embryonic stem cells or adult stem cells and to coax these undifferentiated 
cells into becoming dopamine-producing neurons. Because embryonic stem 
cells are derived from days-old embryos created during in vitro 
fertilization, their use is highly controversial. Fewer ethical questions 
surround the use of adult stem cells, which are harvested from adult 
tissue, but some scientists believe these cells are more difficult to work 
with.

Despite important progress in identifying the molecular cues and recipes 
for pushing undifferentiated cells to produce dopamine, no one yet knows 
whether transplantation of any kind will be as fruitful a strategy as has 
been hoped. The clinical trials using the most meaningful protocols have so 
far been conducted with fetal material. These have shown hundreds of 
thousands of surviving transplanted dopamine-producing cells in patients, 
yet the functional benefits have been at best modest and inconsistent, and 
the treatment has been associated with serious adverse effects, including 
dyskinesias (uncontrollable writhing and twisting movements). Scientists 
are trying to determine why transplantation has not been more helpful and 
why side effects have arisen, but for now they are not conducting human 
trials of the procedure in the U.S.

Finally, researchers continue to investigate and refine the approach behind 
deep-brain stimulation: applying electric pulses. Several months ago 
Stéphane Palfi and his colleagues at the CEA Frédéric Joliot Hospital 
Service in Orsay, France, reported that gently stimulating the brain 
surface could improve symptoms in baboons with a version of Parkinson's. 
Clinical trials are under way in France and elsewhere to determine whether 
this surgical intervention is similarly effective in humans.

Although much remains unknown about Parkinson's, the genetic and cellular 
insights that have come to light in just the past few years are highly 
encouraging. They give new hope for treatments that will combine with 
existing ones to slow disease progression and improve control of this 
distressing disorder.



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