In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Publication date: Available online 1 February 2018 Source:Cell Author(s): Qiang Guo, Carina Lehmer, Antonio Martínez-Sánchez, Till Rudack, Florian Beck, Hannelore Hartmann, Manuela Pérez-Berlanga, Frédéric Frottin, Mark S. Hipp, F. Ulrich Hartl, Dieter Edbauer, Wolfgang Baumeister, Rubén Fernández-Busnadiego Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (poly-GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes. Graphical abstract Teaser Neuronal poly-GA aggregates linked to amyotrophic lateral sclerosis and frontotemporal dementia selecti...
Source: Cell - Category: Cytology Source Type: research

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Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations inMatrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3 ’s zinc finger domains partially m...
Source: eLife - Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research
t S Abstract VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in theC9ORF72 (C9) gene. Previously we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al. 2016). Here we show that this signature also occurs in half of 50 post-mortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these 'like-C9...
Source: eLife - Category: Biomedical Science Tags: Biochemistry and Chemical Biology Human Biology and Medicine Source Type: research
Publication date: Available online 30 June 2018Source: PM&RAuthor(s): Richard D. Zorowitz, David N. Alexander, Andrea E. Formella, Fred Ledon, Charles Davis, Joao SiffertAbstractBackgroundDextromethorphan (DM)/quinidine (Q) was approved for pseudobulbar affect (PBA) treatment based upon efficacy and safety trials in patients with PBA secondary to amyotrophic lateral sclerosis or multiple sclerosis. The PRISM II trial evaluated DM/Q as PBA treatment in patients with stroke, dementia or traumatic brain injury.ObjectiveTo report results from the stroke cohort of PRISM II, including the Stroke Impact Scale (SIS).DesignOpen-lab...
Source: PMandR - Category: Rehabilitation Source Type: research
Publication date: 2018Source: NeuroImage: Clinical, Volume 19Author(s): Monica Consonni, Valeria E. Contarino, Eleonora Catricalà, Eleonora Dalla Bella, Viviana Pensato, Cinzia Gellera, Giuseppe Lauria, Stefano F. CappaAbstractAmyotrophic lateral sclerosis (ALS) can be associated with a spectrum of cognitive and behavioural symptoms, but the related patterns of focal cortical atrophy in non-demented ALS patients remain largely unknown. We enrolled 48 non-demented ALS patients and 26 healthy controls for a comprehensive neuropsychological assessment and a magnetic resonance exam. Behavioural and cognitive impairment ...
Source: NeuroImage: Clinical - Category: Radiology Source Type: research
Publication date: Available online 4 April 2018Source: Neuroscience LettersAuthor(s): Dao K.H. Nguyen, Ravi Thombre, Jiou WangAbstractAge-dependent neurodegenerative diseases are associated with a decline in protein quality control systems including autophagy. Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease of complex etiology with increasing connections to other neurodegenerative conditions such as frontotemporal dementia. Among the diverse genetic causes for ALS, a striking feature is the common connection to autophagy and its associated pathways. There is a recurring theme of protein misfoldin...
Source: Neuroscience Letters - Category: Neuroscience Source Type: research
Publication date: Available online 21 June 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Salinee Jantrapirom, Luca Lo Piccolo, Hideki Yoshida, Masamitsu YamaguchiAbstractThe proteostasis machinery has critical functions in metabolically active cells such as neurons. Ubiquilins (UBQLNs) may decide the fate of proteins, with its ability to bind and deliver ubiquitinated misfolded or no longer functionally required proteins to the ubiquitin-proteasome system (UPS) and/or autophagy. Missense mutations in UBQLN2 have been linked to X-linked dominant amyotrophic lateral sclerosis with fro...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
TANK-binding kinase 1 (TBK1) is a protein playing a critical role in the activation of pro-survival pathways, by phosphorylating Akt, and in autophagy, as its phosphorylation and activation of the autophagic receptors p62 and optineurin is fundamental for the correct cargo recruitment at the forming autophagosome. Moreover, mutations in TBK1 gene have been recently linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In our study we aimed to uncover the molecular pathological mechanisms characterizing ALS patients carrying mutations in TBK1 gene.
Source: Clinical Neurophysiology - Category: Neuroscience Authors: Source Type: research
Abstract Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins imp...
Source: Biochemical Society Transactions - Category: Biochemistry Authors: Tags: Biochem Soc Trans Source Type: research
Publication date: Available online 30 June 2018Source: PM&RAuthor(s): Richard D. Zorowitz, David N. Alexander, Andrea E. Formella, Fred Ledon, Charles Davis, Joao SiffertAbstractBackgroundDextromethorphan (DM)/quinidine (Q) was approved for pseudobulbar affect (PBA) treatment based upon efficacy and safety trials in patients with PBA secondary to amyotrophic lateral sclerosis or multiple sclerosis. The PRISM II trial evaluated DM/Q as PBA treatment in patients with stroke, dementia or traumatic brain injury.ObjectiveTo report results from the stroke cohort of PRISM II, including the Stroke Impact Scale (SIS).DesignOpen-lab...
Source: PMandR - Category: Rehabilitation Source Type: research
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