SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease

Garcia-Reitböck, Pablo; Anichtchik, Oleg; Bellucci, Arianna; Iovino, Mariangela; Ballini, Chiara; Fineberg, Elena; Ghetti, Bernardino; Corte, Laura Della; Spano, PierFranco; Tofaris, George K.; Goedert, Michel; Spillantini, Maria Grazia

doi:10.1093/brain/awq132

Cited by 259 publications

(255 citation statements)

References 40 publications

(53 reference statements)

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“…Phosphorylation of synapsin‐1 triggers neurotransmitter release but is blocked by binding huntingtin protein in HD (Xu et al ., 2013). Syntaxin‐1 is a synaptic SNARE protein that forms age‐ and PD‐dependent co‐aggregates with α‐synuclein (Garcia‐Reitbock et al ., 2010). Tenascin‐R co‐aggregates with APP at nodes of Ranvier on myelinated axons (Xu et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…Finally, mice expressing a truncated form of human SNCA (1-120 SNCA) under the control of the TH promoter in an endogenous null background developed inclusions in the SN, motor abnormalities, redistribution of SNARE proteins and impaired exocytosis [177,178]. Recently, these mice were used to generate a new transgenic line by crossing them with WT mice.…”

Section: Snca (Park1/park4)mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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“…A loss of DCC function is likely to have a more significant impact in neurons requiring high maintenance of axonal and dendritic structural integrity, like ventral SNC neurons. In mice expressing mutant human α-synuclein, there is an age-dependent redistribution of synaptic SNARE proteins and a reduction in dopamine release (Garcia-Reitbock, et al, 2010) that may either be linked to or cause a loss of DCC function. α-Synuclein has been shown to block the activation of the SNARE complex (Darios, et al, 2010), potentially also blocking DCC function (Cotrufo, et al, 2011).…”

Section: Is Found In Higher Amounts In the Ventral Snc Neurons Vumentioning

confidence: 99%

Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease

Reyes

Double

et al. 2013

Neurobiology of Aging

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Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors Pitx3 and Otx2 and the trophic factor receptor DCC, but there is limited information on their expression and localisation in adult humans. Pitx3, Otx2 and DCC were immunohistochemically localised in the upper brainstem of adult humans and mice and protein expression assessed using relative intensity measures and online microarray data. Pitx3 was present and highly expressed in most dopamine neurons. Surprisingly, in our elderly subjects no Otx2 immunoreactivity was detected in dopamine neurons, although Otx2 gene expression was found in younger cases. Enhanced DCC gene expression occurred in the substantia nigra, and higher amounts of DCC protein characterised vulnerable ventral nigral dopamine neurons. Our data show that, at the age when Parkinson's disease typically occurs, there are no significant differences in the expression of transcription factors in brainstem dopamine neurons, but those most vulnerable to Parkinson's disease rely more on the trophic factor receptor DCC than other brainstem dopamine neurons.Key words: deleted in colorectal cancer; dopamine neurons; orthodenticle homeobox 2; Pitx3; substantia nigra Abbreviations: DCC= deleted in colorectal cancer; Otx2= orthodenticle homeobox 2; PD= Parkinson's disease; SNC= substantia nigra pars compacta; TH= tyrosine hydroxylase; VTA= ventral tegmental area Reyes et al. 3

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SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease

Cited by 259 publications

References 40 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease

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