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Topics {✒️}

nitro-blue-toluidine/5-bromo-4-chloro-3-indolyl-phosphate control aav-mir-nt pre-injected abundant ps129-α-syn-labeled cells ps129-α-syn-positive cell counts aav-mir-nt pre-injected mice high-molecular-weight α-synuclein species aav-mir-7 pre-injected + pff mice targeting aav-mir-nt-injected mice ps129-α-syn-immunoreactive inclusions aav1-ef1α-ctl-mir-egfp aav-mir-nt pre-injected ]fluoro-l-m-tyrosine imaging form ps129-α-syn-positive aggregates aav-mir-nt-infused brain sections abundant ps129-α-syn immunoreactivity ps129-α-syn immunoreactive neurons aav-mir-7 pre-injected mice α-syn pff-inoculated side ps129-α-syn-positive cells 1-methyl-4-phenylpyridinium-induced cell death control aav-nt-injected brains aav-mediated α-syn overexpression α-syn pff-inoculated mice alpha-synuclein-induced microglial activation α-synuclein preformed fibrils recruit endogenous α-syn aav-mir-7 pre-injection resulted α-syn pff-inoculated brains sh-sy5y cells lowering α-syn production reducing α-syn levels downregulating α-synuclein levels α-syn pff-inoculated groups intrastriatal alpha-synuclein fibrils regulate α-syn levels aav-mir-7 pre-injected downregulating α-syn levels long-term rnai knockdown pathological α-synuclein initiates anti-α-synuclein aso delivered repressing α-syn levels sonicated α-syn fibrils a53t-aav synuclein rats native α-synuclein protein aav-injected mice showed downregulating α-synuclein expression monomeric α-syn protein including lenti-mir-nt α-syn pff inoculations α-synuclein pff inoculation

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         headline:MicroRNA-7 Protects Against Neurodegeneration Induced by α-Synuclein Preformed Fibrils in the Mouse Brain
         description:α-Synuclein is a key protein in the pathogenesis of Parkinson’s disease as it accumulates in fibrillar form in affected brain regions. Misfolded α-synuclein seeds recruit monomeric α-synuclein to form aggregates, which can spread to anatomically connected brain regions, a phenomenon that correlates with clinical disease progression. Thus, downregulating α-synuclein levels could reduce seeding and inhibit aggregate formation and propagation. We previously reported that microRNA-7 (miR-7) protects neuronal cells by downregulating α-synuclein expression through its effect on the 3′-untranslated region of SNCA mRNA; however, whether miR-7 blocks α-synuclein seeding and propagation in vivo remains unknown. Here, we induced miR-7 overexpression in the mouse striatum unilaterally by infusing adeno-associated virus 1 (AAV-miR-7) followed by inoculation with recombinant α-synuclein preformed fibrils (PFF) a month later. Compared with control mice injected with non-targeting AAV-miR-NT followed by PFF, AAV-miR-7 pre-injected mice exhibited lower levels of monomeric and high-molecular-weight α-synuclein species in the striatum, and reduced amount of phosphorylated α-synuclein in the striatum and in nigral dopamine neurons. Accordingly, AAV-miR-7-injected mice had less pronounced degeneration of the nigrostriatal pathway and better behavioral performance. The neuroinflammatory reaction to α-synuclein PFF inoculation was also significantly attenuated. These data suggest that miR-7 inhibits the formation and propagation of pathological α-synuclein and protects against neurodegeneration induced by PFF. Collectively, these findings support the potential of miR-7 as a disease modifying biologic agent for Parkinson’s disease and related α-synucleinopathies.
         datePublished:2021-10-25T00:00:00Z
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      headline:MicroRNA-7 Protects Against Neurodegeneration Induced by α-Synuclein Preformed Fibrils in the Mouse Brain
      description:α-Synuclein is a key protein in the pathogenesis of Parkinson’s disease as it accumulates in fibrillar form in affected brain regions. Misfolded α-synuclein seeds recruit monomeric α-synuclein to form aggregates, which can spread to anatomically connected brain regions, a phenomenon that correlates with clinical disease progression. Thus, downregulating α-synuclein levels could reduce seeding and inhibit aggregate formation and propagation. We previously reported that microRNA-7 (miR-7) protects neuronal cells by downregulating α-synuclein expression through its effect on the 3′-untranslated region of SNCA mRNA; however, whether miR-7 blocks α-synuclein seeding and propagation in vivo remains unknown. Here, we induced miR-7 overexpression in the mouse striatum unilaterally by infusing adeno-associated virus 1 (AAV-miR-7) followed by inoculation with recombinant α-synuclein preformed fibrils (PFF) a month later. Compared with control mice injected with non-targeting AAV-miR-NT followed by PFF, AAV-miR-7 pre-injected mice exhibited lower levels of monomeric and high-molecular-weight α-synuclein species in the striatum, and reduced amount of phosphorylated α-synuclein in the striatum and in nigral dopamine neurons. Accordingly, AAV-miR-7-injected mice had less pronounced degeneration of the nigrostriatal pathway and better behavioral performance. The neuroinflammatory reaction to α-synuclein PFF inoculation was also significantly attenuated. These data suggest that miR-7 inhibits the formation and propagation of pathological α-synuclein and protects against neurodegeneration induced by PFF. Collectively, these findings support the potential of miR-7 as a disease modifying biologic agent for Parkinson’s disease and related α-synucleinopathies.
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         α-Synucleinopathies
         α-Synuclein
         Pre-formed fibrils
         microRNA-7
         Neurosciences
         Neurology
         Neurosurgery
         Neurobiology
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      name:RWJMS Institute for Neurological Therapeutics and Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, USA
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      name:RWJMS Institute for Neurological Therapeutics and Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, USA
      name:RWJMS Institute for Neurological Therapeutics and Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, USA
      name:RWJMS Institute for Neurological Therapeutics and Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, USA
      name:RWJMS Institute for Neurological Therapeutics and Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, USA

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