Researchers made progress in 2006 along the long road from basic research to new treatments for diseases related to human movement. Laboratory studies of protein folding, inflammation, growth factors, and genetics have suggested new ways to monitor and treat these disorders. Some treatments are now being tested in animals and humans.

Protein Misfolding: Friends or Enemies?

A protein’s shape determines what it does in the body. Cells make proteins composed of long strings of subunits called amino acids, which coil and fold to form three-dimensional shapes. Incorrectly folded proteins do not interact properly with other proteins. Misfolded proteins may also attach to each other and form clumps called inclusions, which are common in the brains of people with some neurological disorders.

Alpha-synuclein is a major component of the inclusions (called Lewy bodies) typically found in brain cells of people with Parkinson’s disease, a disorder that causes rigidity, tremors, and slow movement. Lewy bodies are also found in a related form of dementia called, appropriately, dementia with Lewy bodies. Alpha-synuclein-rich inclusions are also found in multiple system atrophy, which may resemble Parkinson’s disease and cause problems with speech, balance, and coordination.

Two recent studies, by Thomas Südhof and colleagues (reported in Cell) and by Tracey Dickson and colleagues (reported in Experimental Neurology), suggest that the normal function of alpha-synuclein is to protect nerve cells from damage.^1,2 Normal levels of properly folded alpha-synuclein, then, seem to protect cells, but overproduction, misfolding, and aggregation of the protein are associated with disease. How?

Although there is some controversy on the issue, it is generally believed that protein misfolding and aggregation contribute to cell death, but the process remains unclear. It may be that the misfolded proteins are unable to do their normal jobs, but they also appear to interfere with the cell’s other functions. A study led by Richard Morimoto, reported in Science, suggests that an excess of misfolded proteins can overwhelm the cell’s “quality control” system, resulting in misfolding of other proteins.³ Another study, by Susan Lindquist and colleagues and published in Science, suggests that excess alpha-synuclein interferes with the movement of proteins within cells.⁴

1. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, and Südhof TC. Alpha-synuclein cooperates with CSP-alpha in preventing neurodegeneration. Cell 2005 123(3):383–396.

2. Quilty MC, King AE, Gai WP, Pountney DL, West AK, Vickers JC, and Dickson TC. Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Experimental Neurology 2006 199(2):249–256.

3. Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, and Morimoto RI. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 2006 311(5766):1471–1474.

4. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, and Lindquist S. Alpha-synuclein blocks ER-golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006 313(5785):324–328.

5. Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG. Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington’s and Parkinson’s diseases. Proceedings of the National Academy of Sciences USA 2006 103(11):4246–4251.

6. Cookson, MR. Hero vs. antihero: The multiple roles of alpha-synuclein in neurodegeneration. Experimental Neurology 2006 199(2):238–242.

7. Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, and Rocca WA. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: A case-control study. Neurology 2006 67(3):494–496.

8. Hernán MA, Logroscino G, and García Rodriguez LA. Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease. Neurology 2006 66(7):1097–1099.

9. Alano CC, Kauppinen TM, Valls AV, and Swanson RA. Minocycline inhibits poly (ADP-ribose) polymerase-1 at nanomolar concentrations. Proceedings of the National Academy of Sciences USA 2006 103(25):9685–9690.

10. The NINDS NET-PARKINSON’S DISEASE Investigators. A randomized, double-blind, futility clinical trail of creatine and minocycline in early Parkinson disease Neurology 2006 66(5):664–671.

11. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, and Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006 441(7097):1157–1161.

12. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, and Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006 441(7097):1162–1166.

13. Sun M, Latourelle JC, Wooten GF, Lew MF, Klein C, Shill HA, Golbe LI, Mark MH, Racette BA, Perlmutter JS, Parsian A, Guttman M, Nicholson G, Xu G, Wilk JB, Saint-Hilaire MH, DeStefano AL, Prakash R, Williamson S, Suchowersky O, Labelle N, Growdon JH, Singer C, Watts RL, Goldwurm S, Pezzoli G, Baker KB, Pramstaller PP, Burn DJ, Chinnery PF, Sherman S, Vieregge P, Litvan I, Gillis T, MacDonald ME, Myers RH, and Gusella JF. Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease. Archives of Neurology 2006 63(6):826–832.

14. Hedrich K, Hagenah J, Djarmati A, Hiller A, Lohnau T, Lasek K, Grunewald A, Hilker R, Steinlechner S, Boston H, Kock N, Schneider-Gold C, Kress W, Siebner H, Binkofski F, Lencer R, Munchau A, and Klein C. Clinical spectrum of homozygous and heterozygous PINK1 mutation in a large family with Parkinson disease. Archives of Neurology 2006 63(6):833–838.

15. Zadikoff C, Rogaeva E, Djarmati A, Sato C, Salehi-Rad S, St George-Hyslop P, Klein C, and Lang AE. Homozygous and heterozygous PINK1 mutations: considerations for diagnosis and care of Parkinson’s disease patients. Movement Disorders 2006 21(6): 875–879.

16. Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, Brooks DJ, and Piccini P. Microglial activation correlates with severity in Huntington’s disease. A clinical and PET study. Neurology 2006 66(11):1638–1643.

17. Chebrolu H, Slevin JT, Gash DA, Gerhardt GA, Young B, Given CA, and Smith CD. MRI volumetric and intensity analysis of the cerebellum in Parkinson’s disease patients infused with glial-derived neurotrophic factor (GDNF). Experimental Neurology 2006 198(2):450–456.

18. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, and Traub M. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Annals of Neurology 2006 59(3):459–466.

19. Slevin JT, Gash DM, Smith CD, Gerhardt GA, Kryscio R, Chebrolu H, Walton A, Wagner R, and Young AB. Unilateral intraputaminal glial cell line-derived neurotrophic factor in patients with Parkinson disease: Response to 1 year each of treatment and withdrawal. Neurosurgical Focus 2006 20(5):E1–E7.

20. McBride JL, Ramaswamy S, Gasmi M, Bartus RT, Herzog CD, Brandon EP, Zhou L, Pitzer MR, Berry-Kravis EM, and Kordower JH. Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease. Proceedings of the National Academy of Sciences USA 2006 103(24):9345–9350.

21. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2006 66(3):366–372.