Decoding ALS: from genes to mechanism

Taylor, J. Paul; Brown, Robert H.; Cleveland, Don W.

doi:10.1038/nature20413

Cited by 1,632 publications

(1,666 citation statements)

References 154 publications

(176 reference statements)

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“…A similar transition can lead to aberrant stress granule dynamics of C9orf72‐derived dipeptide repeats, which plays a role in the pathogenesis in amyotrophic sclerosis (ALS; Taylor et al , 2016). In different neurodegenerative diseases such as AD and FTD, hyperphosphorylated tau is found in pathological tau aggregates (Gong et al , 2005), and the phosphorylation pattern of p‐tau441 has been shown to be similar to that found in tau aggregates from AD brains (Mair et al , 2016).…”

Section: Resultsmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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“…Motor neuron death in ALS often occurs in association with protein inclusions. Familial ALS accounts for 10% of cases and has been associated with mutations in the SOD1 gene and ubiquitin-related genes (155). Glutamate levels are elevated in ALS patient cerebrospinal fluid, possibly because of aberrant expression of the astrocytic glutamate transporter EAAT2 (156).…”

Section: Immune-directed Therapies For Neurodegenerative Diseasesmentioning

confidence: 99%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

386

240

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“…Dipeptide repeat protein accumulations and/or RNA inclusions have been shown to impair nucleocytoplasmic transport in affected cells (100-102); however, ongoing studies are needed to determine the connection between nucleocytoplasmic transport defects and selective neuronal death in ALS/FTD. Potential gain-of-function mechanisms were recently reviewed elsewhere (103,104). surveillance cells of the brain and are highly sensitive to changes in their environment.…”

Section: C9orf72 In Als/ftdmentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

142

102

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Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

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Decoding ALS: from genes to mechanism

Cited by 1,632 publications

References 154 publications

Tau protein liquid–liquid phase separation can initiate tau aggregation

Tau protein liquid–liquid phase separation can initiate tau aggregation

CNS inflammation and neurodegeneration

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

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