PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but the molecular mechanisms controlling these events are not completely understood. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator known as master regulator of mitochondrial functions and oxidative metabolism. Recent studies, including one from our group, have highlighted altered PGC-1α activity and transcriptional deregulation of its target genes in PD pathogenesis suggesting it as a new potential therapeutic target. Resveratrol, a natural polyphenolic compound proved to improve mitochondrial activity through the activation of several metabolic sensors resulting in PGC-1α activation. Here we have tested in vitro the effect of resveratrol treatment on primary fibroblast cultures from two patients with early-onset PD linked to different Park2 mutations. We show that resveratrol regulates energy homeostasis through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) and raise of mRNA expression of a number of PGC-1α's target genes resulting in enhanced mitochondrial oxidative function, likely related to a decrease of oxidative stress and to an increase of mitochondrial biogenesis. The functional impact of resveratrol treatment encompassed an increase of complex I and citrate synthase activities, basal oxygen consumption, and mitochondrial ATP production and a decrease in lactate content, thus supporting a switch from glycolytic to oxidative metabolism. Moreover, resveratrol treatment caused an enhanced macro-autophagic flux through activation of an LC3-independent pathway. Our results, obtained in early-onset PD fibroblasts, suggest that resveratrol may have potential clinical application in selected cases of PD-affected patients.

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

Freezing is a well-known problem in Parkinson''s disease (PD) and is characterized by an abrupt difficulty in starting or continuing rhythmic and repetitive movements. We utilized a questionnaire in order to assess the occurrence of the freezing gait phenomenon (FG) in a population of 100 consecutive PD patients. Our PD population included 70 males and 30 females, with a mean age of 61.1 ± 9.1 years. Mean duration of PD was 6.5 ± 4.0 years. 92/100 patients were under L-Dopa treatment. The FG phenomenon occurred in 60% of patients. It appeared on average 4.8 years after the beginning of PD; in 16% of the cases it was evident before starting L-Dopa treatment. FG was more frequent among female patients. There was no significant correlation between the occurrence of FG and the age of the patients; on the other hand, a significant correlation was found with the duration of the disease (p < 0.001). FG occurred more frequently in the subgroup of patients with the akinetic form (odds ratio: 3.05); whilst an opposite tendency was evident in the subgroup with the tremor predominant form (odds ratio: 0.29).

Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw-Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands-Ligue Européene Contre la Maladie d'Alzheimer (LECMA).

No abstract

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment, and dementia. Elevated plasma concentrations of Hcy have been found recently in Parkinson's disease (PD) patients treated with levodopa, suggesting that levodopa is a cause of hyperhomocysteinemia (HHcy). The mechanism underlying HHcy in PD is the O-methylation of levodopa catalyzed by catechol-O-methyltransferase (COMT) that produces S-adenosylhomocysteine, which is hydrolyzed rapidly to Hcy. COMT inhibitors (COMT-I) are used currently in the treatment of PD; however, no study has assessed the effects of COMT-I administration on Hcy concentrations in PD patients. We compared plasma levels of Hcy, B12, and folate in 26 PD patients treated with levodopa, 20 PD patients treated with levodopa + COMT-I, and 32 controls. No significant differences were found in vitamin B12 levels, whereas folate concentrations were significantly lower in the levodopa-treated group. Plasma Hcy was increased significantly in the two groups of PD patients and was significantly lower in the group treated with levodopa + COMT-I. Statistical analysis showed that the difference in mean Hcy levels observed among PD patients was related to the addition of COMT-I, rather than to folate concentrations. We conclude that levodopa treatment increases plasma Hcy and the addition of COMT-I effectively reduces HHcy.

ABSTRACT:Objective: To study the frequency, clinical features and clinical genetics of familial Parkinson's disease (PD). Methods: Family history for PD and tremors was studied in 100 consecutive PD cases. Spouses served as controls. Clinical features were compared between personally verified familial and sporadic PD cases, from the same consecutive clinical series. Clinical genetic analysis was performed in a larger group of non-consecutive multicase PD families. Results: Family history for PD was positive in 24% of consecutive PD cases and in 6% of spouse controls (p < 0.001). When family history for isolated tremor is also considered, the number of positive cases rises to 43% compared with 9% in controls (p < 0.001). Nine of the consecutive cases had at least one living affected relative, for a total of 20 familial PD cases. These familial cases showed an earlier onset age when compared with sporadic ones from the same consecutive series. Within 22 non-consecutive PD families with at least two living and personally examined PD cases (total 52 PD cases), the crude segregation ratios were similar for parents and siblings and the lifetime cumulative risks approached 0.4 in siblings and tended to be comparable, but at later ages, in parents. Ancestral relatives were all unilaterally distributed. In some families, anticipation of onset age in new generations was observed. Conclusions: The frequency of positive family history for PD and for PD and tremor is higher among PD cases than controls. Familial and sporadic PD only differ in onset age. The clinical genetic analyses support autosomal dominant inheritance with strongly age-related penetrance as most likely in familial PD. RESUME: Maladie de Parkinson familiale: analyse genetique clinique. Objectif: Iitudier la frequence, les manifestations cliniques et la gen&ique clinique de la maladie de Parkinson familiale (MP). Methodes: Nous avons fitudie l'histoire familiale quant a la MP et au tremblement chez 100 cas consecutifs de MP. Les conjoints ont servi de controles. Nous avons compare les manifestations cliniques entre les cas familiaux et sporadiques de MP confirmed personnellement, dans cette meme sene de cas. Nous avons proc6de a une analyse genefique clinique chez un groupe plus considerable de families comprenant plusieurs cas de MP non consecutifs. Resultats: L'histoire familiale dtait positive chez 24% des cas consecutifs de MP et chez 6% des conjoints servant de controles (p < 0.001). Quand nous tenons egalement compte d'une histoire familiale de tremblement, le nombre de cas positifs s'61eve a 43% compart a 9% chez les controles (p < 0.001). Neuf des cas consecutifs avaient au moins un membre vivant de sa famille qui 6tait atteint, pour un total de 20 cas de MP familiale. Ces cas familiaux pr&entaient un age de ddbut plus precoce compart aux cas sporadiques de la meme serie de cas consecutifs. Dans 22 families de MP non consecutives comprenant au moins deux cas de MP vivants et examines personnellement (pour un total de 52 cas de MP), le ratio de segre...