RESUMO
Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.
Assuntos
Adenosina Trifosfatases/genética , Glucosilceramidas/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Neurônios Dopaminérgicos/metabolismo , Feminino , Glucosilceramidase/genética , Glucosilceramidas/genética , Humanos , Corpos de Lewy/patologia , Lisossomos/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismoAssuntos
Demência/genética , Distonia/genética , Mutação da Fase de Leitura/genética , Transtornos Parkinsonianos/genética , ATPases Translocadoras de Prótons/genética , Criança , Demência/complicações , Demência/diagnóstico , Distonia/complicações , Distonia/diagnóstico , Humanos , Masculino , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico , Linhagem , Gravação em VídeoRESUMO
The relative contribution of simple mutations and copy number variations (CNVs) in SNCA, PARK2, PINK1, PARK7, and LRRK2 to the genetic etiology of Parkinson disease (PD) is still unclear because most studies did not completely analyze each gene. In a large group of Belgian PD patients (N = 310) and control individuals (N = 270), we determined the mutation frequency of both simple mutations and CNVs in these five PD genes, using direct sequencing, multiplex amplicon quantification (MAQ), and real-time PCR assays. Overall, we identified 14 novel heterozygous variants, of which 11 were absent in control individuals. We observed eight PARK2 (multiple) exon multiplications in PD patients and one exon deletion in a control individual. Furthermore, we identified one SNCA whole-gene duplication. The PARK2 and LRRK2 mutation frequencies in Belgian PD patients were similar to those reported in other studies. However, at this stage the true pathogenic nature of some heterozygous mutations in recessive genes remains elusive. Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful.
Assuntos
Dosagem de Genes , Mutação , Doença de Parkinson/genética , Bélgica/epidemiologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Frequência do Gene , Genética Populacional , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Proteínas Oncogênicas/genética , Proteína Desglicase DJ-1 , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , alfa-Sinucleína/genéticaRESUMO
The aetiology of Parkinson's disease (PD) is unknown and said to be multifactorial. We report on a retrospective epidemiological case control study, performed in Flanders during a 3-year period, investigating known and potential environmental risk factors for PD by means of questionnaires. We investigated 423 prevalent patients and 205 spouse-controls. We found familial occurrence in 15% of the patients, a mean age of onset of 58 years, and a clear male preponderance (male/female ratio 1.53). Our results suggest more nulliparity among female PD patients (95% CI: 1.08-5.76). We found a discrete clustering of patients in areas with intensive metallurgic frequently employed in metallurgy than controls (95% CI: 1.04-9.20). Furthermore, patients were clearly more exposed to zinc (95% CI: 1.51-90.90) and toluene (95% CI: 1.03 58.82). Male patients report more prostatectomy-surgery (95% CI: 1.54-17.24).