D<scp>NAJC</scp>6<scp>M</scp>utations <scp>A</scp>ssociated <scp>W</scp>ith <scp>E</scp>arly‐<scp>O</scp>nset <scp>P</scp>arkinson's <scp>D</scp>isease

Olgiati, Simone; Quadri, Marialuisa; Fang, Mingyan; Rood, Janneke P.M.A.; Saute, Jonas Alex Morales; Chien, Hsin Fen; Bouwkamp, Christian G.; Graafland, Josja; Minneboo, Michelle; Breedveld, Guido J.; Zhang, Shiping; Verheijen, Frans W.; Boon, Agnita J.W.; Kievit, Anneke J.A.; Jardim, Laura Bannach; Mandemakers, Wim; Barbosa, Egberto Reis; Rieder, Carlos Roberto de Mello; Leenders, Klaus L.; Wang, Jun; Bonifati, Vincenzo

doi:10.1002/ana.24553

Cited by 147 publications

(67 citation statements)

References 48 publications

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“…(Bonifati, 2014). The clinical phenotype of DNAJC6-mediated PD includes a rapid disease course with poor response to L-DOPA, pyramidal signs, seizures, mental retardation, and dystonia (Olgiati et al, 2016). Patients with pathogenic SYNJ1 mutations also present with a rapid disease course; however, progression stabilizes in later stages of the disease.…”

Section: Other Rare Arpd Genesmentioning

confidence: 99%

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott

Dawson

2017

Experimental Neurology

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Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.

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Section: Other Rare Arpd Genesmentioning

confidence: 99%

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott

Dawson

2017

Experimental Neurology

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“…Several recent studies have revealed a link between proteins that participate in synaptic vesicle endocytic recycling, clathrin mediated endocytosis in particular, and early onset Parkinsonism (EOP) (Edvardson et al, 2012; Koroglu et al, 2013; Krebs et al, 2013; Olgiati et al, 2014; Olgiati et al, 2016; Quadri et al, 2013; Schreij et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

“…In these patients Parkinson-like symptoms developed in early adulthood (20–30’s) and 4 of them additionally suffered from epilepsy (Drouet and Lesage, 2014). This finding is of striking interest, as loss-of-function mutations in the gene DNAJC6 that encode auxilin, another protein that functions in the uncoating of endocytic CCVs (Fotin et al, 2004; Ungewickell et al, 1995), are also responsible for autosomal recessive juvenile Parkinson’s disease (PD) and sporadic cases of PD, leading to define auxilin as PARK19 (Edvardson et al, 2012; Koroglu et al, 2013; Olgiati et al, 2016). Based on studies of the purified protein, the EOP mutation of SJ1 (SJ1 R->Q ) selectively abolishes the phosphatase activity of the Sac domain without affecting the activity of the 5-phosphatase domain (Krebs et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons

Cao

Ashrafi

et al. 2017

Neuron

138

180

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SUMMARY Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1’s 5-phosphatase module in this process is well established, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset Parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin coated intermediates strongly implicating Sac domain’s activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson’s disease.

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“…By sequencing the DNAJC6 gene in patients with early-onset PD, Olgiati et al discovered three patients with double mutations in this gene [76••]. Two of them had familial disease, and analysis of affected and unaffected family members showed complete co-segregation.…”

Section: New Genes For Recessive and X-linked Pd Or Parkinsonismmentioning

confidence: 99%

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

Puschmann

2017

Curr Neurol Neurosci Rep

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Purpose of ReviewThis article reviews genes where putative or confirmed pathogenic mutations causing Parkinson’s disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.Recent FindingsNewly reported genes for dominant Parkinson’s disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. SummaryMutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson’s disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.

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DNAJC6Mutations Associated With Early‐Onset Parkinson's Disease

Cited by 147 publications

References 48 publications

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

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