V Bonifati

..The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD...

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..1. Suggestive linkage to an overlapping region of chromosome 14q was reported in a recent scan of TS sibling pairs. This region might therefore contain an important gene for TS, and it should be prioritized for further study...

..Other Mendelian genes remain to be found, but the complete resolution of the genetic architectures of the common PD forms represents the main challenge for the next decade...

..Although much work remains to be done to clarify the biology of DJ-1, its proposed activity as a molecular chaperone and/or as oxidative sensor appear intriguing in the light of the current theories on the pathogenesis of PD...

..The success of this method in several common diseases leaves little doubt that it will aid in deciphering the genetic bases of the most common and devastating neurodegenerative disorders...

..To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism...

..Collectively, these discoveries highlight a substantial overlap between the known genetic determinants of Parkinson's disease and DLB, as well as the presence of profound etiologic heterogeneity in Lewy body disorders...

..Moreover, we focus on the mechanisms of disease caused by alpha-synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease...

..Yet, it is expected that other monogenic forms of parkinsonism will be identified in the future, as mutations in the above-mentioned genes are not found in other patients with similar phenotypes...

..To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD)...

..Understanding how the dysfunction of LRRK2 protein leads to neurodegeneration might provide crucial insights for unraveling the molecular mechanisms of PD and for developing disease-modifying therapies...

..The importance of genetic testing is expected to increase in the near future in the PD field. Here, the author provides a brief update on the genetics of the monogenic forms of PD...

..These data have important implications for the diagnostic work-up and genetic counseling of patients with this disease in Portugal...

..However, the optimism generated by the initial report has quickly been tempered by results obtained in the first wave of follow-up studies...

..The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls...

..Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations...

..In conclusion, the frequency of mutations in the parkin gene in certain populations might be high enough to cause allelic heterogeneity in the same sibship...

..This will contribute to unraveling the pathogenesis of AREP, and it is also expected to foster our understanding of molecular events underlying classic Parkinson's disease...

..We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls...

..Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease...

..This study confirms the frequent involvement of parkin and the importance of genetic testing in the diagnostic work-up of EOP...

..Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease...

..These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice...

..Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism...

..The associated phenotype was broad, including early and late disease onset. These findings confirm the association of LRRK2 with neurodegeneration, and identify a common mutation associated with dominantly inherited Parkinson's disease...

..Our findings suggest that the LRRK2 Gly2385Arg is the first identified, functionally relevant variant, which acts as common risk factor for sporadic PD in the population of Chinese ethnicity...

..Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause...

..Our data add to a growing body of evidence suggesting that GIGYF2 mutations are not a frequent cause of PD...

..After 27 years of follow-up, 4788 subjects are still alive. The aim of this study is to measure the prevalence of Parkinson's disease in a large group of workers with theoretically increased risk...

..We conclude that the UCH-L1 gene is not a major gene responsible for familial PD...

..We review advances in the genetics of Parkinson's disease, focusing on the monogenic forms and their clinical and population-genetic consequences...

..The LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinson's disease. Knowledge of its worldwide frequency distribution is essential for clinical and molecular research as well as genetic counseling...

..Our study extends the view that different neurodegenerative diseases may have similar pathological mechanisms, and that these processes likely include DJ-1...

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..7-6.1, P < 0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q...

..Assignment of families to either PARK6 or PARK7 might be difficult because of the proximity of the two loci on chromosome 1p...

..These findings confirm that recessive mutations in PINK1 cause early-onset parkinsonism and expand the associated clinical phenotype...

..In conclusion, we provide the first confirmation of the RLS-5 locus, and we reduce its critical region. The identification of the underlying mutation might reveal an important susceptibility gene for this common movement disorder...

..The negative results of the SLITRK1 analysis point to genetic heterogeneity in TS...

..Whether the Gly2385Arg variant modifies the risk for MSA deserves further study in larger samples...

..LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2?..

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..1366C>T mutation...

..These findings support the concept that the neurodegeneration associated with LRRK2 mutations might be clinically and pathologically indistinguishable from typical PD...

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..Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations...

..This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD...

..This rapid turnover and the structural changes of DJ-1L166P mutant protein might be crucial in the disease pathogenesis...

..We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's disease...

..This suggests that apolipoprotein E4 is responsible for the linkage peak in this region and that it is a modest risk factor for Parkinson's disease...

..RT-PCR experiments revealed that the parkin gene is expressed in sural nerves from both controls and patient with parkin-related disease. Our findings support the view that parkin may play a role in the peripheral nervous system...

..The identification of an 85-year-old, healthy Gly2019Ser carrier supports the concept that this mutation displays incomplete penetrance...

..Nevertheless, our results suggest that further investigation in GSTP1 variants and PD pathogenesis is warranted in sporadic PD and that a search for toxins that accelerate PD OA should pay particular attention to GST-P1 substrates...

..Clinical features in carriers were those of typical, idiopathic Parkinson's disease. However, behavioural abnormalities were frequent (87%), suggesting a more widespread limbic involvement in G2019S carriers...

..PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients...

..We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD...

..The cluster reported here, which to our knowledge is the largest described to date with early-onset PD and parkin mutations, also offers a unique opportunity for the search of modifiers of the parkin-related disease...

..Therefore, PARK11 does not seem to play a major role for familial PD in the European population...