Relação entre fatores genéticos envolvidos em vias metabólicas mitocondriais e a doença de Parkinson

A doença de Parkinson (DP) é uma das desordens neurodegenerativas mais comuns associada ao envelhecimento, alcançando 2% aos 70 anos. É uma doença caracterizada pela degeneração progressiva de neurônios dopaminérgicos nigrais nos gânglios basais e pela presença de inclusões protéicas citoplasmáticas denominadas corpúsculos e neuritos de Lewy nos neurônios sobreviventes. A etiologia da DP é pouco conhecida, sendo considerada, na maioria dos casos, idiopática. Conhecimentos alcançados nos últimos 15 anos sobre a base genética da DP demonstram, claramente, que os fatores genéticos desempenham um importante papel na etiologia desta desordem. Neste trabalho, rastreamos mutações nos genes que codificam proteínas participantes de vias metabólicas mitocondriais (Parkin, PINK1 e DJ-1) em 136 pacientes brasileiros com manifestação precoce da DP, através do sequenciamento automático e da técnica de MLPA. Avaliamos a presença de variantes de sequência por meio do sequenciamento dos exons 1 a 12 do gene Parkin e dos exons 1 a 8 do gene PINK1. Em Parkin foram identificadas três mutações patogênicas ou potencialmente patogênicas, ambas em heterozigose: p.T240M, p.437L e p.S145N. Em PINK1 não encontramos variantes de ponto patogênicas. Através da técnica de MLPA investigamos alterações de dosagem nos genes Parkin, PINK1 e DJ-1. Identificamos cinco alterações no gene Parkin em quatro pacientes: uma duplicação heterozigota do exon 4 no paciente PAR2256, uma deleção heterozigota do exon 4 no probando PAR2099, uma deleção homozigota do exon 4 na paciente PAR3380 e um probando heterozigoto composto (PAR2396) com duas alterações, uma duplicação do exon 3 e uma deleção dos exons 5 e 6. No gene PINK1 identificamos uma deleção heterozigota do exon 1, que nunca foi descrita na literatura, em um paciente (PAR2083). Não encontramos alteração quantitativa no gene DJ-1. Neste estudo obtivemos uma frequência total de mutações patogênicas (pontuais e de dosagem) nos genes estudados de 7,3%, sendo 6,6% no gene Parkin e 0,7% no gene PINK1.

Investigação de variantes exônicas nos genes VPS35, EIF4G1 e LRRK2 como causa da doença de Parkinson em casuística brasileira

A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais frequente no mundo, afetando 1-2% da população acima de 65 anos, caracterizada clinicamente por tremor em repouso, bradicinesia, instabilidade postural e rigidez muscular. Essas manifestações surgem devido à degeneração neuronal progressiva e à presença de inclusões proteicas ricas em α-sinucleína. A DP é decorrente da interação entre fatores ambientais e genéticos, e entre os fatores genéticos, variantes exônicas de transmissão dominante nos genes LRRK2 (leucine-rich repeat kinase 2), VPS35 (vacuolar protein sorting 35) e EIF4G1 (eukaryotic translation initiation factor 4-gamma 1) têm sido associadas à etiologia da doença. Entretanto, estudos sobre o efeito dessas variantes na população brasileira são raros ou inexistentes. Por essa razão, neste trabalho rastreamos mutações nos genes VPS35 (p.D620N; p.R524W), EIF4G1 (p.R1205H; p.A502V) e LRRK2 (p.G2019S) em uma amostra de 582 pacientes brasileiros com DP não aparentados e 329 indivíduos controles saudáveis. Além disso, conduzimos o primeiro estudo caso-controle para análise de variantes exônicas raras (p.Q1111H, p.T1410M, p.M1646T, p.S1761R, p.Y2189C) e comuns (p.N551K, p.R1398H, p.K1423K) no gene LRRK2 em um subgrupo de 329 pacientes brasileiros com DP, não aparentados, naturais da região sudeste. Esse subgrupo foi analisado e comparado com 222 indivíduos controles saudáveis a fim de verificar associações dessas variantes e a DP. Em relação às mutações dos genes VPS35 e EIF4G1, não foram encontradas alterações nos pacientes com DP. A mutação p.G2019S no gene LRRK2 foi encontrada em 15 probandos (2,6%), dos quais 9 são do sexo feminino (64,3%). O tremor em repouso foi observado em 47,36% dos pacientes com a mutação p.G2019S como primeiro sintoma motor. As análises das variantes raras no gene LRRK2 não revelaram qualquer associação estatisticamente significante. Entre as variantes comuns, a p.K1423K mostrou evidência de associação de risco com a DP (p<0,05) na estratificação contendo o grupo de indivíduos com história familiar da doença e para as variantes p.N551K e p.R1398H não foram observadas associações. A análise do haplótipo p.N551K-p.R1398H-p.K1423K revelou associação de proteção na amostra sudeste e na estratificação Rio de Janeiro (p<0,05). Esse haplótipo não está em desequilíbrio de ligação na amostra de 222 indivíduos controles brasileiros analisados (r2≤45). Os resultados obtidos neste estudo representam contribuições valiosas ao entendimento da relação entre as variantes genéticas estudadas e o risco de desenvolvimento da doença de Parkinson, principalmente no que se refere aos endofenótipos associados.

The Effect of Motivation on Movement: A Study of Bradykinesia in Parkinson's Disease

Background: Bradykinesia is a cardinal feature of Parkinson's disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes. Methodology/Principal Findings: We developed a novel movement time paradigm involving winnable rewards and avoidable painful electrical stimuli. The faster the subjects performed an action the more likely they were to win money (in appetitive blocks) or to avoid a painful shock (in aversive blocks). We compared PD patients when OFF dopaminergic medication with controls. Our key finding is that PD patients OFF dopaminergic medication move faster to avoid aversive outcomes (painful electric shocks) than to reap rewarding outcomes (winning money) and, unlike controls, do not speed up in the current trial having failed to win money in the previous one. We also demonstrate that sensitivity to distracting stimuli is valence specific. Conclusions/Significance: We suggest this pattern of results can be explained in terms of low dopamine levels in the Parkinsonian state leading to an insensitivity to appetitive outcomes, and thus an inability to modulate movement speed in the face of rewards. By comparison, sensitivity to aversive stimuli is relatively spared. Our findings point to a rarely described property of bradykinesia in PD, namely its selective regulation by everyday outcomes. © 2012 Shiner et al.

Dopamine and performance in a reinforcement learning task: evidence from Parkinson's disease.

The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson's disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning.

Dopamine and performance in a reinforcement learning task: Evidence from Parkinson's disease

The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson's disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning. © 2012 The Author.

“Ana”: Apología de la enfermedad como estilo de vida

SIN FINANCIACIÓN

Prestaciones ocupacionales/laborales para personas con enfermedad mental. Estudio comparativo por CCAA

El estigma y la discriminación que sufren las personas con enfermedad mental y discapacidad dan como resultado dificultades de incorporación socio-laboral, situaciones de vulnerabilidad y exclusión social. En este documento se recogen, visualizan y comparan las diferentes prestaciones del ámbito ocupacional y laboral destinadas a las personas con enfermedad mental y discapacidad derivada de ésta de las siguientes Comunidades Autónomas uniprovinciales de España: Asturias, Cantabria, La Rioja, Madrid, Murcia y Navarra. A través del mismo, se puede conocer la situación laboral de las personas con enfermedad mental y discapacidad derivada de ésta y aclarar los tipos de Centros y programas específicos que hay para este colectivo en las diferentes Comunidades estudiadas. Se elaboran y aportan al trabajo tablas comparativas de síntesis de resultados para obtener una visión global de la situación estudiada.

Expression and function of the neurotrophic factors GDF5 and GDNF in the nigrostriatal system during development and in rat models of Parkinson's disease

Growth/differentiation factor 5 (GDF5) and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that promote the survival of midbrain dopaminergic neurons in vitro and in vivo. Both factors have potent neurotrophic and neuroprotective effects in rat models of Parkinson's disease (PD), and may represent promising new therapies for PD. The aim of the present study was to investigate the endogenous expression and function of GDF5 and GDNF in the nigrostriatal dopaminergic system during development and in rat models of PD. Examination of the temporal expression patterns of endogenous GDF5, GDNF, and their respective receptors, in the developing and adult nigrostriatal dopaminergic system suggest that these factors play important roles in promoting the survival and maturation of midbrain dopaminergic neurons during the period of postnatal programmed cell death. The relative levels of GDF5 and GDNF mRNAs in the midbrain and striatum, and their individual temporal expression patterns during development, suggest that their modes of actions are quite distinct in vivo. Furthermore, the sustained expression of GDF5, GDNF, and their receptors into adulthood suggest roles for these factors in the continued support and maintenance of mature nigrostriatal dopaminergic neurons. The present study found that endogenous GDF5, GDNF, and their receptors are differentially expressed in two 6-hydroxydopamine-induced lesion adult rat models of PD. In both terminal and axonal lesion models of PD, GDF5 mRNA levels in the striatum increased at 10 days post-lesion, while GDNF mRNA levels in the nigrostriatal system decreased at 10 and 28 days post-lesion. Thus, despite the fact that exogenous GDF5 and GDNF have similar effects on midbrain dopaminergic neurons in vitro and in vivo, their endogenous responses to a neurotoxic injury are quite distinct. These results highlight the importance of studying the temporal dynamic changes in neurotrophic factor expression during development and in animal models of PD.

The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.

G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D(2) dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA.

Clinical traits of LRRK2-associated parkinson's disease in ireland: a link between familial and idiopathic PD

The role of genetics in parkinsonism has been confirmed over the last decade with the identification of genetic variation in seven genes, which are causative in familial forms of the disorder. A number of pathogenic mutations have been identified in the latest gene LRRK2, with a Gly2019Ser amino acid substitution identified in two siblings and one patient with idiopathic Parkinson's disease from Ireland. The clinical features resemble the idiopathic variant with a tremor predominant clinical picture shared by the siblings, slow progression of symptoms, and no observation of cognitive disturbance in all. The family and the sporadic individual were apparently not related and originated from different regions of Ireland, although haplotype analysis does suggest they share a common founder. The influence of the G2019S substitution on protein function and disease phenotype has yet to be fully resolved, but its elucidation will undoubtedly further our understanding of the mechanisms underlying Parkinson's disease.

Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders.

An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, alpha-synuclein (alpha-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of alpha-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of alpha-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit alpha-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.