What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease

Olga Corti; Suzanne Lesage; Alexis Brice

doi:10.1152/physrev.00022.2010

journal article Oct 01, 2011

What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease

Olga Corti Suzanne Lesage

Alexis Brice

Physiological Reviews Vol. 91 No. 4 pp. 1161-1218 · American Physiological Society

View at Publisher Save 10.1152/physrev.00022.2010

Abstract

Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.

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References

718

[1]

10.1016/s0140-6736(10)62345-8

[2]

10.1002/mds.23265

[3]

10.1016/s0896-6273(00)80886-7

[4]

10.1002/ana.10675

[5]

10.1056/nejmoa033277

[6]

10.1016/j.parkreldis.2009.09.010

[7]

10.1212/01.wnl.0000271080.53272.c7

[8]

10.1093/hmg/ddp346

[9]

10.1074/jbc.m207825200

[10]

10.1111/j.1468-1331.2007.02052.x

[11]

10.1074/jbc.m600933200

[12]

10.1073/pnas.0703219104

[13]

10.1523/jneurosci.0979-08.2008

[14]

10.1006/bbrc.2000.4113

[15]

10.1126/science.1067389

[16]

AzeredodaSilveira S Hum Mol Genet (2009)

[17]

Baba M Am J Pathol (1998)

[18]

10.1007/s10048-009-0186-0

[19]

10.1371/journal.pone.0001884

[20]

10.1016/j.mcn.2004.06.014

[21]

10.1212/01.wnl.0000278109.76607.0a

[22]

10.1523/jneurosci.2218-08.2008

[23]

10.1073/pnas.0500617102

[24]

10.1038/ng1769

[25]

10.1093/brain/116.6.1451

[26]

10.1074/jbc.274.48.33855

[27]

10.1002/mds.20504

[28]

10.1093/brain/awh666

[29]

10.1093/hmg/ddp384

[30]

10.1016/0022-510x(73)90175-5

[31]

10.1016/j.bcmd.2005.07.005

[32]

10.1016/j.neulet.2005.07.045

[33]

10.1016/s0140-6736(89)90291-2

[34]

10.1212/01.wnl.0000267844.72421.6c

[35]

10.1002/ana.21019

[36]

10.1074/jbc.m806599200

[37]

10.1002/mds.22640

[38]

10.1126/science.1077209

[39]

10.1212/01.wnl.0000317005.06662.01

[40]

10.1016/j.bbamcr.2003.08.008

[41]

10.1002/ana.20937

[42]

10.1212/wnl.52.6.1214

[43]

10.1093/hmg/ddn340

[44]

10.1002/mds.20682

[45]

Bretaud S J Neurochem (2007) 10.1111/j.1471-4159.2006.04291.x

[46]

10.1136/jmg.2008.063917

[47]

10.1212/01.wnl.0000338439.00992.c7

[48]

10.1016/j.parkreldis.2008.11.014

[49]

10.1021/bi036135+

[50]

10.1523/jneurosci.22-20-08797.2002

Showing 50 of 718 references

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Details

Published: Oct 01, 2011
Vol/Issue: 91(4)
Pages: 1161-1218

Authors

O

Olga Corti

Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U.975; Centre National de la Recherche Scientifique, UMR 7225; and AP-HP, Hôpital de la Salpêtrière, Department of Genetics and Cytogenetics, Paris, France

S

Suzanne Lesage

Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U.975; Centre National de la Recherche Scientifique, UMR 7225; and AP-HP, Hôpital de la Salpêtrière, Department of Genetics and Cytogenetics, Paris, France

A

Alexis Brice

Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U.975; Centre National de la Recherche Scientifique, UMR 7225; and AP-HP, Hôpital de la Salpêtrière, Department of Genetics and Cytogenetics, Paris, France

Cite This Article

Olga Corti, Suzanne Lesage, Alexis Brice (2011). What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease. Physiological Reviews, 91(4), 1161-1218. https://doi.org/10.1152/physrev.00022.2010

What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease

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