Considerations Regarding the Etiology and Future Treatment of Autosomal Recessive Versus Idiopathic Parkinson Disease Authors
Movement Disorders (O Suchowersky, Section Editor)
First Online: 01 May 2012 DOI:
Cite this article as: Kitada, T., Tomlinson, J.J., Ao, H.S. et al. Curr Treat Options Neurol (2012) 14: 230. doi:10.1007/s11940-012-0175-8 Opinion statement
We postulate that the frequently encountered grouping of different Parkinson disease (PD) variants into a single pathogenetic concept—rather than differentiation into its molecular subtypes—has hindered progress toward curative interventions. Parkinsonism is a clinical syndrome that in rare cases can be explained by a single genetic event or by a single environmental cause, thereby leading to monogenic PD and secondary parkinsonism, respectively. Under the former category, mutations in both alleles of the Parkin-encoding
PARK2 gene leads to young-onset, autosomal recessive PD, in which neurodegeneration is restricted to dopamine-producing cells of the brainstem. Under the latter category, exposure to one of several environmental factors with neuroanatomic selectivity can cause rapid-onset, secondary parkinsonism most likely irrespective of the patient’s age and genetic makeup. Sandwiched between these two extreme and rare types, the most common variant is referred to as late-onset, idiopathic PD. In extension of a disease model first proposed by Braak et al., we consider idiopathic PD the result of an encounter between one or several environmental triggers and one or more susceptibility alleles. Importantly, this interaction produces a pre-motor syndrome followed by the typical PD phenotype over a period of decades. In our opinion, this pathophysiological process should thus be viewed as a “complex disease.” As is true for many complex human disorders, successful intervention for the common PD variant will likely occur when genetic leads as well as environmental contributors are targeted in parallel. However, successful proof-of-concept studies could arrive sooner, namely for select PD variants that can be attributed to a single genetic event and that are neuropathologically restricted. Therefore, the authors decided to focus the second portion of their review on treatment considerations regarding autosomal recessive PD cases that are caused by Parkin deficiency. We briefly draw attention to aspects of existing pharmacological and surgical therapies as they relate to the PARK2-linked variant; thereafter, we comment on new research avenues that are aimed at future therapeutic interventions to eventually slow or arrest the progression of a first variant of PD. Keywords alpha-synuclein Parkin LRRK2 GBA1 Parkinson disease Parkinsonism
Tohru Kitada and Julianna J. Tomlinson contributed equally.
References and Recommended Reading
Tarsy D. Initial treatment of Parkinson’s disease. Curr Treat Options Neurol. 2006;8(3):224–35.
Bertoni JM, Prendes JL, Sprenkle P. Long-term Medical Treatment for Parkinson’s Disease. Curr Treat Options Neurol. 2001;3(6):495–506.
Hinson VK. Parkinson’s disease and motor fluctuations. Curr Treat Options Neurol. 2010;12(3):186–99.
Rao J. Treatment of Levodopa-induced Dyskinesia. Curr Treat Options Neurol. 2007;9(3):205–9.
Bronte-Stewart H. Parkinson’s Disease: Surgical Options. Curr Treat Options Neurol. 2003;5(2):131–47.
Wilkinson JR, Weintraub D, and Stern MB. Clinical Manifestations of Parkinson’s Disease. In: Watts RL, Standaert DG, and Obeso JA, editors. Movement Disorders, 3rd Edition. McGraw-Hill; 2012. p. 229–46.
Hughes AJ et al. JNNP 1992;55:181–184.
Bernheimer H, et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20(4):415–55.
Yamamura Y, et al. Paralysis agitans of early onset with marked diurnal fluctuation of symptoms. Neurology. 1973;23(3):239–44.
Braak H, et al. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003;110(5):517–36.
Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: the dual hit theory revisited. Ann N Y Acad Sci. 2009;1170:615–22.
Zimprich A, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–7.
Pramstaller PP, et al. Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol. 2005;58(3):411–22.
Schlossmacher MG, Mollenhauer B. Biomarker research in Parkinson’s disease: objective measures needed for patient stratification in future cause-directed trials. Biomark Med. 2010;4(5):647–50.
Klein C, et al. Translational research in neurology and neuroscience 2011: movement disorders. Arch Neurol. 2011;68(6):709–16.
Klein C, Schlossmacher MG. The genetics of Parkinson disease: Implications for neurological care. Nat Clin Pract Neurol. 2006;2(3):136–46.
Marras C, and Tanner CM. Epidemiology of Parkinson’s disease. In: Watts RL, Standaert DG, and Obeso JA, editors. Movement Disorders, 3rd Edition, McGraw-Hill; 2012. p. 169–92.
Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet. 2006;7:306–18.
Klein C, et al. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 2007;6(7):652–62.
Kordower JH, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008;14(5):504–6.
Li JY, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501–3.
Mollenhauer B, et al. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2008;213(2):315–25.
Sidransky E, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651–61.
Sardi SP, et al. Mutant GBA1 expression and Synucleinopathy risk: First insights from cellular and mouse models. Neurodegener Dis, 2012.
Eblan MJ, Walker JM, Sidransky E. The glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med. 2005;352(7):728–31. author reply 728–31.
Tomlinson JJ, Cullen V, and Schlossmacher MG. Identifying targets in alpha-Synuclein metabolism to treat Parkinson’s and related disorders, in protein misfolding diseases: Current and emerging principles and therapies, In: Ramirez-Alvaro M, Kelly JW, and Dobson CM, editors. Wiley & Sons 2010.
Lee BD, et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med. 2010;16(9):998–1000.
Liu Z, et al. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol. 2011;12(11):1063–70.
Hakimi M, et al. Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm. 2011;118(5):795–808.
Moehle MS, et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci. 2012;32(5):1602–11.
Salat-Foix D, et al. Gastrointestinal symptoms in Parkinson disease: clinical aspects and management. Can J Neurol Sci. 2011;38(4):557–64.
Mutez E, et al. Transcriptional profile of Parkinson blood mononuclear cells with LRRK2 mutation. Neurobiol Aging. 2011;32(10):1839–48.
Nalls MA, et al. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377(9766):641–9.
Kitada T, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392(6676):605–8.
Shimura H, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25(3):302–5.
Narendra DP, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8(1):e1000298.
Khan NL, et al. Parkin disease: a phenotypic study of a large case series. Brain. 2003;126(Pt 6):1279–92.
Lucking CB, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med. 2000;342(21):1560–7.
Gandhi S, et al. PINK1 protein in normal human brain and Parkinson’s disease. Brain. 2006;129(Pt 7):1720–31.
Klein C, et al. Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: Expanding the phenotype. Ann Neurol. 2000;48(1):65–71.
Oliveira SA, et al. Parkin mutations and susceptibility alleles in late-onset Parkinson’s disease. Ann Neurol. 2003;53(5):624–9.
Fox SH, et al. The movement disorder society evidence-based medicine review update: Treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2011;26 Suppl 3:S2–41.
Seppi K, et al. The movement disorder society evidence-based medicine review update: Treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. 2011;26 Suppl 3:S42–80.
Grimes DA. Canadian guidelines on Parkinson’s disease (on behalf of the Canadian Parkinson’s Research Alliance). Can J Neurol Sci, 2012 (in press).
Lohmann E, et al. Are parkin patients particularly suited for deep-brain stimulation? Mov Disord. 2008;23(5):740–3.
Moro E, et al. Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism. Neurology. 2008;70(14):1186–91.
de Bruin N, et al. Walking with music is a safe and viable tool for gait training in Parkinson’s disease: the effect of a 13-week feasibility study on single and dual task walking. Parkinsons Dis. 2010;2010:483530.
Horstink M, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol. 2006;13(11):1170–85.
Ulusoy A, Kirik D. Can overexpression of parkin provide a novel strategy for neuroprotection in Parkinson’s disease? Exp Neurol. 2008;212(2):258–60.
Witt J, Marks Jr WJ. An update on gene therapy in Parkinson’s disease. Curr Neurol Neurosci Rep. 2011;11(4):362–70.
Kato S, et al. Efficient gene transfer via retrograde transport in rodent and primate brains using a human immunodeficiency virus type 1-based vector pseudotyped with rabies virus glycoprotein. Hum Gene Ther. 2007;18(11):1141–51.
Preynat-Seauve O, et al. Pluripotent stem cells as new drugs? The example of Parkinson’s disease. Int J Pharm. 2009;381(2):113–21.
Allan LE, Petit GH, Brundin P. Cell transplantation in Parkinson’s disease: problems and perspectives. Curr Opin Neurol. 2010;23(4):426–32.
Soldner F, et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell. 2011;146(2):318–31.
Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7(1):97–109.
Chan CS, et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature. 2007;447(7148):1081–6.
Murata M. The discovery of an antiparkinsonian drug, zonisamide. Rinsho Shinkeigaku. 2010;50(11):780–2.
Murata M. Zonisamide: a new drug for Parkinson’s disease. Drugs Today (Barc). 2010;46(4):251–8.
Storch A, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64(7):938–44.
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