Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease

Polymeropoulos, Mihael H.; Lavedan, Christian; Leroy, Elisabeth; Ide, Susan; Dehejia, Anindya; Dutra, Amalia; Pike, Brian L.; Root, Holly; Rubenstein, Jeffrey S.; Boyer, R; Stenroos, Edward S.; Chandrasekharappa, Settara C.; Athanassiadou, Aglaia; Papapetropoulos, Theodore; Johnson, William G.; Lazzarini, Alice; Duvoisin, Roger C.; Iorio, Giuseppe Di; Golbe, Lawrence I.; Nussbaum, Robert L.

doi:10.1126/science.276.5321.2045

Cited by 7,583 publications

(5,273 citation statements)

References 20 publications

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“…Direct assessment of ER membranes from WT and AT‐1 sTg mice revealed a marked increase in the acetylation status of Atg9a in the transgenic animals (Figure 5a,b), thus supporting our hypothesis. To assess whether the increased acetylation of Atg9a was accompanied by reduced disposal of misfolded/aggregated ER cargo proteins, we took advantage of the pro‐aggregating properties of the A53 T mutant form of α‐synuclein (A53 T syn; Polymeropoulos et al, 1997). Specifically, we used A53 T syn with a signal peptide (SP) at the N‐terminus to direct translation on the ER and insertion into the secretory pathway (Peng et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

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Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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“…Also proteins like alpha‐synuclein (α‐synuclein), which has long been implicated in the pathogenesis of PD (Polymeropoulos et al, 1997) could act as both modulators of glial functions and as antigens themselves activating the peripheral and central immune system (Harms et al, 2013; Reynolds et al, 2008; Sanchez‐Guajardo et al, 2015). Thus in PD itself, α‐synuclein itself might be an antigen used by MHC II during antigen presentation and thus leading to the observed glial infiltration in PD (Hunot and Hirsch, 2003).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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“…Mis‐sense mutations13, 36, 37, 38, 39, 40 and duplications or triplications of the SNCA gene, which encodes αS, lead to autosomal dominant early onset PD 41, 42. It has previously been shown that the formation of αS oligomers in vitro is concentration dependent,12 and ADPAINT now enables us to determine whether this dependence is reflected in cellular models that overexpress αS.…”

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confidence: 99%

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

et al. 2018

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The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. These aggregates are highly heterogeneous in structure, generally of low abundance and typically smaller than the diffraction limit of light (≈250 nm). To overcome the challenges these characteristics pose to the study of endogenous aggregates formed in cells, we have developed a method to characterise them at the nanometre scale without the need for a conjugated fluorophore. Using a combination of DNA PAINT and an amyloid‐specific aptamer, we demonstrate that this technique is able to detect and super‐resolve a range of aggregated species, including those formed by α‐synuclein and amyloid‐β. Additionally, this method enables endogenous protein aggregates within cells to be characterised. We found that neuronal cells derived from patients with Parkinson's disease contain a larger number of protein aggregates than those from healthy controls.

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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease

Cited by 7,583 publications

References 20 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

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