Axonal transport defects are a common phenotype in<i>Drosophila</i>models of ALS

Baldwin, Katie R.; Godena, Vinay K.; Hewitt, Victoria L.; Whitworth, Alexander J.

doi:10.1093/hmg/ddw105

Cited by 85 publications

(107 citation statements)

References 59 publications

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“…In addition to mutations in TDP-43 and SOD1, inherited forms of ALS can be caused by mutated FUS or repeat expansions in the C9orf72 gene (Peters et al, 2015). In a recent report (Baldwin et al, 2016), expression of mutant TDP-43, FUS and C9orf72, or knockout of the homologs of these genes, in Drosophila resulted in axonal transport deficits. Importantly, these axonal transport deficits manifested as motor deficits that generally worsened with age in most of the Drosophila models.…”

Section: Evidence Of Mt Abnormalities In Other Neurodegenerative Condmentioning

confidence: 97%

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Brunden

Lee

Smith

et al. 2017

Neurobiology of Disease

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Many neurodegenerative diseases are characterized by deficiencies in neuronal axonal transport, a process in which cellular cargo is shuttled with the aid of molecule motors from the cell body to axonal termini and back along microtubules (MTs). Proper axonal transport is critical to the normal functioning of neurons, and impairments in this process could contribute to the neuronal damage and death that is characteristic of neurodegenerative disease. Although the causes of axonal transport abnormalities may vary among the various neurodegenerative conditions, in many cases it appears that the transport deficiencies result from a diminution of axonal MT stability. Here we review the evidence of MT abnormalities in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and traumatic brain injury, and highlight the potential benefit of MT-stabilizing agents in improving axonal transport and nerve function in these diseases. Moreover, we discuss the challenges associated with the utilization of MT-stabilizing drugs as therapeutic candidates for neurodegenerative conditions.

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Section: Evidence Of Mt Abnormalities In Other Neurodegenerative Condmentioning

confidence: 97%

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Brunden

Lee

Smith

et al. 2017

Neurobiology of Disease

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“…Using an enzyme-linked immunosorbent assay (ELISA), we could detect both poly-GA and poly-GP in all the C9orf72 lines (Fig. S5E), confirming that RAN translation is occurring in these cells.Defective microtubule-based transport of mitochondria in axons has been linked with a variety of neurodegenerative diseases (42), including ALS caused by other mutations (43)(44)(45)(46)(47). We therefore assessed motility of these organelles by live imaging of C9orf72 and healthy control motor neuron lines incubated with the mitochondrial stain, Mitotracker.Kymograph-based analysis of neurons that had been differentiated for 38 days revealed that the proportion of mitochondria undergoing transport in neurites was reduced in the C9orf72 lines ( Fig.…”

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confidence: 99%

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Fumagalli

Young

Boeynaems

et al. 2019

Preprint

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Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies. INTRODUCTIONA GGGGCC (G4C2) repeat expansion in the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD) (1,2). Since the association between the hexanucleotide repeat expansions (HREs) and these neurodegenerative diseases was discovered, three non-mutually exclusive pathological mechanisms have been proposed. The first is a loss-of-function scenario due to decreased expression of C9orf72 transcript and protein observed in C9-ALS/FTD patients (1,3). The second is an RNA gain-of-function mechanism caused by the accumulation of expanded repeat transcripts that sequester numerous RNA-binding proteins (4-9). The third proposed mechanism is a protein gain-of-function via the generation of pathological dipeptide repeat proteins (DPRs) originating from non-ATG mediated translation of the expanded repeat transcripts (10-13).This repeat-associated non-ATG (RAN) translation occurs in all reading frames of sense and antisense transcripts resulting in five DPR proteins: poly-GR and poly-GA exclusively from the sense transcript, poly-PR and poly-PA exclusively from the antisense transcript, and poly-GP from both transcripts (10-13). DPRs are found in cytoplasmic inclusions in C9-ALS/FTD post-mortem brain and spinal cord tissue, and also have been detected in motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) (5,10,11,(14)(15)(16)(17)(18). The arginine-rich DPRs -poly-PR and poly-GR -are potently toxic in numerous disease models (14,(19)(20)(21)(22)(23)(24)(25)(26)(27), and have been shown to cause mitochondrial (28,29) and endoplasmic reticulum stress (26), as well as disturbances...

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“…As a consequence, mutant FUS/Caz impairs axonal transport of synaptic vesicle proteins, thus reducing the level of Synaptotagmin, a key component of the presynaptic release machinery. Disruption of axonal transport has been identified in multiple models of ALS and other neurodegenerative diseases, but whether it’s a causative factor, a participating pathogenic mechanism, or a consequence of neurodegeneration remains unclear (Baldwin et al, 2016; Bilsland et al, 2010; De Vos et al, 2008; Marinkovic et al, 2012). Overexpression of FUS has previously been shown to disrupt transport of mitochondria in Drosophila motor neurons (Chen et al, 2016), with the most severe disruption seen in mutant FUS-expressing animals.…”

Section: Discussionmentioning

confidence: 99%

FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons

et al. 2018

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Mutations in the nuclear localization signal of the RNA binding protein FUS cause both Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). These mutations result in a loss of FUS from the nucleus and the formation of FUS-containing cytoplasmic aggregates in patients. To better understand the role of cytoplasmic FUS mislocalization in the pathogenesis of ALS, we identified a population of cholinergic neurons in Drosophila that recapitulate these pathologic hallmarks. Expression of mutant FUS or the Drosophila homolog, Cabeza (Caz), in class IV dendritic arborization neurons results in cytoplasmic mislocalization and axonal transport to presynaptic terminals. Interestingly, overexpression of FUS or Caz causes the progressive loss of neuronal projections, reduction of synaptic mitochondria, and the appearance of large calcium transients within the synapse. Additionally, we find that overexpression of mutant but not wild type FUS results in a reduction in presynaptic Synaptotagmin, an integral component of the neurotransmitter release machinery, and mutant Caz specifically disrupts axonal transport and induces hyperexcitability. These results suggest that FUS/Caz overexpression disrupts neuronal function through multiple mechanisms, and that ALS-causing mutations impair the transport of synaptic vesicle proteins and induce hyperexcitability.

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Axonal transport defects are a common phenotype inDrosophilamodels of ALS

Cited by 85 publications

References 59 publications

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons

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