**6. References**


transport, autophagy (mitophagy), and mitochondrial stress (Figure 2). In addition, a prionlike transmission of α-synuclein may trigger the development of nigral degeneration in PD. Taken together, the new findings based on the interaction between familial PD-related proteins and environmental factors could shed light on the pathomechanisms for PD.

Fig. 2. Summary of pathogenetic factors involved in Parkinson's disease (PD). Recent evidence indicated that the PINK1/Parkin pathway participates in mitochondrial removal via autophagy (mitophagy). LRRK2 may associate with cell signaling pathways and the membrane trafficking system. Several environmental factors, such as MPTP, paraquat, and rotenone are known as mitochondrial toxins. In addition, a prion-like transmission of α-

This study was supported in part by grants for research on diseases of the brain from the

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Ministry of Education, Science and Sports in Japan.

**5. Acknowledgments** 

**6. References** 


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**2** 

Celeste Sassi

*1USA 2UK* 

**Genetics of Parkinson Disease** 

*1Laboratory of Neurogenetics, National Institute on Aging,* 

*2Department of Molecular Neuroscience and Reta Lila Weston Institute,* 

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder second to Alzheimer's disease, affecting 1-2% of individuals over 60 years of age,

Its phenotypic complexity, characterized by motor (resting tremor, bradikinesia, rigidity and postural instability) and non-motor (autonomic dysfunction and cognitive impairment) symptoms lead to the description of this disorder as a syndrome rather than a monolithic disease. Genetic research in the past 10 years, in particular mapping and cloning of genes which cause the inherited form of the disease, has shown that "Parkinson syndrome" is not one disease entity but rather an atherogeneous group of disorders that are associated with a spectrum of clinical and pathological changes. It is believed to be caused by the interaction

There is a growing body of evidence that genetic risk factors are of major importance in PD.

Familial PD is caused by very rare highly age penetrant mutations, inherited in a Mendelian way (autosomal recessive or dominant). The biological effect of these mutations is sufficient

Sporadic PD is a complex multifactorial disease in which very common genetic variants play a very modest role singularly while taken all together, interacting with other genes and environmental factors, they can exert an important cumulative effect leading to the

In the last decade pathogenic mutations in five genes (*SNCA*, *LRRK2, PRKN, DJ-1* and *PINK1*) have been linked to familial PD. Recently genome wide association studies, GWAS, across different populations identified other 6 loci involved in the sporadic disease (*MAPT, SNCA*, *HLA-DRB5*, *BST1*, *GAK* and *LRRK2*). Finally a meta-analysis of the 5 previous GWAS discovered 5 new loci in association with the idiopatic disease (*ACMSD*, *STK39*, *MCCC1/LAMP3*, *SYT11* and *CCDC62/HIP1R*) (International Parkinson Disease Genomics

of environmental factors and genetic variants acting on the stage of an aging brain.

PD can be referred mostly as sporadic (90-95%) and to a lesser extent as familial (5%)

**1. Introduction** 

with a risk that increases with age.

So far 16 loci have been identified involved in PD.

alone for the development of the disease.

development of the disease.

Consortium, 2011)

*National Institutes of Health, Bethesda,* 

*UCL Institute of Neurology, London,* 


Celeste Sassi

*1Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 2Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, 1USA 2UK* 
