Research into Huntington’s disease and Parkinson’s disease in 2007 brought the genetic and molecular underpinnings of these movement disorders more clearly into view but also revealed their dazzling complexity, thereby tempering excitement about treatment advances. Deeper understanding of both diseases depends on greater insights into the molecular activity taking place within brain cells, researchers say.
People who develop Huntington’s disease are born with the gene mutation that causes the disease, but many do not develop symptoms until they are in their forties. This long lag has puzzled scientists, but explanations have begun to emerge.
In one of the most provocative insights into Huntington’s disease during 2007, Cynthia T. McMurray and colleagues at the Mayo Clinic and elsewhere traced the disease process to the routine oxidation and repair of DNA, which has long been known to play a key role in the aging process itself.
Throughout life, oxygen atoms attach to nucleotides in the ribbon of DNA in each cell. Enzymes in the cell snip out those oxidized fragments and repair the DNA. In a paper in Nature, McMurray demonstrates that in people who carry the Huntington’s disease mutation, this process results in an expansion of the number of repeats of a sequence of three bases—cytosine, adenine, and guanine (CAG)—present at birth on chromosome 4.1 This sequence provides instructions for the manufacture of the huntingtin protein, crucial for transporting neurotransmitters from the cell body down the axon to the synapse, where communication between cells takes place.
Normally, people have between 10 and 35 CAG repeats on chromosome 4. People who have 40 or more CAG repeats eventually develop symptoms of Huntington’s, and the greater the number of repeats, the earlier symptoms tend to appear. For example, a child with 95 repeats developed seizures, cognitive decline, and neuromuscular disorders by the age of 3 and died of Huntington’s disease at age 11.
The normal repair of DNA tends to increase the number of CAG repeats, according to McMurray. She blames this effect on a single enzyme known as OGG1, which causes neurons to produce an increasingly toxic form of the huntingtin protein containing too much glutamine, an amino acid crucial for cell metabolism. The extra glutamine makes the huntingtin protein sticky, causing it to clump together and create debris within the nucleus. This leads to a cascade of cell dysfunction that eventually produces the symptoms of Huntington’s disease.
Brain scans show the dramatic difference between a healthy individual (left) and one with Huntington's disease (right). (Cynthia McMurray)
This observation coincides with the linear relationship between the number of CAG repeats and the age of disease onset. Those born with a large number of CAG repeats develop symptoms early, whereas those born with a smaller number of repeats do not develop symptoms until this DNA repair process has had time to expand the number of CAG repeats to a more toxic level.
In mice that lack the OGG1 enzyme, CAG expansion was powerfully suppressed with no ill effects, suggesting that DNA repair could be carried out by “backup” enzymes. Thus, this enzyme appears to be specifically responsible for promoting CAG expansion, suggesting that if OGG1 somehow could be blocked in humans, the damage caused by Huntington’s disease could be significantly postponed or even prevented.
Taking a different approach, researchers at Cambridge and Harvard have attempted to mitigate the toxic effects of mutant huntingtin protein by coaxing cells to remove toxic debris more efficiently.
In a paper published in Nature Chemical Biology, Stuart L. Schreiber, David C. Rubinsztein, and colleagues report that administering what they call “small-molecule enhancers” to yeast stimulates autophagy, a process by which cells dispose of defective and misfolded proteins such as mutant huntingtin.2 If autophagy could be stimulated in people with Huntington’s disease, it would do nothing to slow or stop the production of huntingtin, but by clearing toxic debris from the cells more effectively, it might postpone the onset of symptoms, the researchers believe.
But mutated huntingtin protein appears to cause numerous other problems, which Elena Cattaneo and colleagues at the University of Milan are studying.
For example, normal huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a protein that supports existing neurons and encourages the growth of synapses and new neurons. In people with Huntington’s disease, neurons in the striatum die, producing spasticity and many other symptoms. In 2001 Cattaneo and colleagues demonstrated that levels of BDNF are known to be lower in people with Huntington’s.3
In 2007, they expanded on that discovery by attributing the dysfunction to a genetic regulatory site that affects BDNF in people with Huntington’s disease.4 However, the site is located in a region of more than 1,000 genes that affect more than just BDNF, suggesting that other genes that affect neurons may be dysfunctional in people with Huntington’s. Currently Cattaneo’s team is looking for molecules that will mimic the activity of normal huntingtin and increase the expression of BDNF and related genes. So far they have identified three compounds that increase the production of BDNF in cells affected by Huntington’s disease.5
BDNF also appears to regulate the development of synapses by increasing the amount of cholesterol in synaptic vesicles.6 In 2005, Cattaneo and colleagues found that cells and tissues in people with Huntington’s had too little cholesterol and that adding cholesterol to the striatal neurons most affected by the disease prevented their death.7 In a 2007 paper in Human Molecular Genetics, Cattaneo and colleagues report that mice with a model of Huntington’s disease also show a lack of cholesterol, and they attribute this deficiency to the same mutant huntingtin protein found in people with Huntington’s.8
The researchers suspect that BDNF signaling directly affects cholesterol biosynthesis, a hypothesis that unifies two seemingly separate dysfunctions.
And while a cure for Huntington’s disease must await a form of genetic engineering that will fix the DNA repeats that result in faulty huntingtin protein, a recent study in mice found that a small molecule known as C2-8 may inhibit the aggregation of mutant huntingtin within cells, which would at least slow the development of symptoms.9
Researchers developed two novel ways to treat Parkinson’s disease in 2007, raising hopes of at least alleviating symptoms such as tremors and muscle rigidity.
Researchers at Northwestern University reported in Nature that they could “rejuvenate” dopamine-producing neurons in a brain region called the substantia nigra pars compacta. These neurons die in people with Parkinson’s, thereby depriving the brain of enough neurotransmitter to maintain normal movement.10
These cells ordinarily use calcium channels to maintain normal metabolism. However, James Surmeier and colleagues found that mice bred without calcium channels functioned normally because their dopamine-producing cells continued to use their sodium channels, which are normally active only in youth.
They applied isradipine, a calcium channel inhibitor, to block the calcium channels in neurons taken from normal mice. For about 30 minutes the cells ceased functioning. Then they resumed their pacemaking activity as the dormant sodium channels began functioning again. When the researchers implanted pellets of isradipine below the skin in mice bred to have symptoms of Parkinson’s disease, the mice did not develop the motor deficits characteristic of the disease.
Further evidence that isradipine may be helpful comes from the fact that it belongs to a class of drugs used to treat hypertension. A retrospective study suggests that patients with hypertension treated with these drugs have a lower incidence of Parksinson’s.11
A failure of the mitochondria, the energy-producing vesicles inside of cells, is another possible cause of the breakdown of dopamine-producing neurons. Researchers at Stanford showed that a mutation in a gene known as pink1 correlates with a higher incidence of Parkinson’s disease.12 When they bred fruit flies with this mutation, the fruit flies’ flight muscles, as well as their dopamine-producing neurons, degenerated.
The muscle degeneration was preceded by abnormalities in the mitochondria, which produce energy for the cell. Mitochondrial dysfunction has been suspected in Parkinson’s disease, the authors say, because pesticides known to increase the risk of the disease inhibit mitochondria. However, flies bred to overexpress parkin, a protein involved in the clearing of misfolded proteins, did not develop these problems, suggesting that pink1 and parkin operate in a common pathway that regulates mitochondrial function and cell survival in fruit flies.
In the realm of treatment, research in 2007 suggested hope for gene therapy. In the first gene therapy study for Parkinson’s, it produced significant improvement with no ill effects.13 Researchers at New York–Presbyterian Hospital/Weill Cornell Medical Center implanted a harmless virus bearing a gene for an enzyme called glutamic acid decarboxylase (GAD) into 12 patients. GAD produces GABA, a neurotransmitter that quells excessive neuronal firing and promotes coordinated movements.
The harmless, GAD-bearing virus was implanted in the subthalamic nucleus at the center of the brain, which regulates movement, in hopes of boosting the production of GABA and thereby restoring normal function, according to lead author Michael Kaplitt. (In 2003, Kaplitt performed the world’s first gene therapy surgery for Parkinson’s.)
To minimize possible risk, the harmless virus was implanted in only one side of the brain, but because patients have symptoms on both sides of their body equally, this technique also provided a way to recognize and measure improvement. Three months after the surgery the patients as a group showed a 25 to 30 percent improvement in movement according to the Unified Parkinson’s Disease Rating Scale. Some showed improvement of 40 to 65 percent.
Such impressive improvement puts interest in this potential therapy in the company of deep brain stimulation, which is already widely used to control the gait disturbances and movement problems of Parkinson’s disease (see also Neuroethics, page 45) in patients to extend the window of therapeutic effectiveness.
Deep brain stimulation holds out the greatest immediate promise for Parkinson’s patients. The therapy involves implanting electrodes deep within the brain, in a region called the subthalamic nucleus. These electrodes are then stimulated to modify electrical communication of nerve cells within and among brain circuits. Through this process, deep brain stimulation blocks the uncontrolled signals that produce the motor symptoms of Parkinson’s, especially tremor.
In 2007 researchers in Italy expanded upon deep brain stimulation by placing electrodes in a new area, the pedunculopontine nucleus, that plays an important role in walking.14 Six patients with Parkinson’s who had not responded well to medication safely responded to electrodes that stimulated the pedunculopontine nucleus at 25 Hz and the subthalamic nucleus at 185 Hz. Patients improved overall by more than 60 percent as measured by the rating scale—well above the improvement achieved by stimulation of either brain area alone, or by medication.
Deep brain stimulation is now an approved and accepted therapy in Parkinson’s disease patients whose symptoms can no longer be treated with L-DOPA, or whose side effects from long-term L-DOPA medication have become debilitating.
For deep brain stimulation, scientists continue to study where in the brain electrodes will alleviate symptoms most effectively. Another recent study found that deep brain stimulation may even have a neuroprotective effect on the dopamine-producing cells in the substantia nigra that degenerate in the disease.15
1. Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, and McMurray CT. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 2007 447(7143):447–452.
2. Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL, Webster JA, Lewis TA, O’Kane CJ, Schreiber SL, and Rubinsztein DC. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nature Chemical Biology 2007 3:331–307.
3. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, and Cattaneo E. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001 293(5529):493–498.
4. Zuccato C, Belyaev N, Conforti P, Ooi L, Tartari M, Papadimou E, MacDonald M, Fossale E, Zeitlin S, Buckley N, and Cattaneo E. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. Journal of Neuroscience 2007 27(26):6972–6983.
5. Rigamonti D, Bolognini D, Mutti C, Zuccato C, Tartari M, Sola F, Valenza M, Kazantsev AG, and Cattaneo E. Loss of Huntingtin function complemented by small molecules acting as repressor element 1/Neuron restrictive silencer element silencer modulators. Journal of Biological Chemistry 2007 282(34):24554–24562.
6. Suzuki S, Kiyosue K, Hazama S, Ogura A, Kashihara M, Hara T, Koshimizu H, and Kojima M. Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development. Journal of Neuroscience 2007 27(24):6417–6427.
7. Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, Strand A, Tarditi A, Woodman B, Racchi M, Mariotti C, DiDonato S, Corsini A, Bates G, Pruss R, Olson JM, Sipione S, Tartari M, and Cattaneo E. Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. Journal of Neuroscience 2005 25(43):9932–9939.
8. Valenza M, Carroll JB, Leoni V, Bertram LN, Bjorkhem I, Singaraja RR, DiDonato S, Lutjohann D, Hayden MR, and Cattaneo E. Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation. Human Molecular Genetics 2007 16:2187–2198.
9. Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, and Hersch S. A small-molecule therapeutic lead for Huntington’s disease: Preclinical pharmacology and efficacy of C2-8 in the R6/s transgenic mouse. Proceedings of the National Academy of Sciences 2007 104(42):16685–16689.
10. Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, and Surmeier DJ. “Rejuvenation” protects neurons in mouse models of Parkinson’s disease. Nature 2007 447:1081–1086.
11. Rodnitzky RL. Can calcium antagonists provide a neuroprotective effect in Parkinson’s disease? Drugs 1999 57(6):845–849.
12. Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang JW, Yang L, Beal MF, Vogel H, and Lu B. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proceedings of the National Academy of Sciences 2007 103(28):10793–10798.
13. Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, Bland RJ, Young D, Strybing K, Eidelberg D, and During MJ. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: An open label, phase I trial. Lancet 2007 369(9579):2097–2105.
14. Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, and Mazzone P. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 2007 130(6):1596–1607.
15. Wallace BA, Ashkan K, Heise CE, Foote KD, Torres N, Mitrofanis J, and Benabid AL. Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys. Brain 2007 130(8):2129–2145.
back to top