Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.Methods and analysesProtocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.Ethics and disseminationThe study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

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Novel TARDBP missense mutation caused familial amyotrophic lateral sclerosis with frontotemporal dementia and parkinsonism

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.05.017 ◽

2021 ◽

Author(s):

Sheng Chen ◽

Rui-Ling Zhou ◽

Wei Zhang ◽

Chun-Hui Che ◽

Shu-Yan Feng ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Missense Mutation ◽

Familial Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

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Frontotemporal dementia and amyotrophic lateral sclerosis: Revisiting one of the first case reports with neuropathological examination

Dementia & Neuropsychologia ◽

10.1590/s1980-57642014dn81000013 ◽

2014 ◽

Vol 8 (1) ◽

pp. 83-86 ◽

Cited By ~ 2

Author(s):

Ricardo Nitrini

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Motor Neurons ◽

Case Reports ◽

Rare Event ◽

Motor Impairments ◽

Late 20Th Century ◽

First Case ◽

Lateral Sclerosis ◽

Neuropathological Examination

ABSTRACT The occurrence of dementia in amyotrophic lateral sclerosis (ALS) was only widely recognized in the late 20th century. Hitherto, it was believed that dementia was a rare event due to the fortuitous association with other diseases. In 1924, Kostantin Nikolaevich Tretiakoff and Moacyr de Freitas Amorim reported a case of dementia with features of frontotemporal dementia (FTD) that preceded the motor signs of ALS. Neuropathological examination confirmed ALS and found no signs of other dementia-causing diseases. The authors hypothesized that dementia was part of ALS and recommended the search for signs of involvement of motor neurons in cases of dementia with an ill-defined clinical picture, a practice currently accepted in the investigation of cases of FTD. This was one of the first descriptions of dementia preceding the motor impairments of ALS and was published in Portuguese and French in Memórias do Hospício de Juquery.

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Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.767041 ◽

2021 ◽

Vol 14 ◽

Author(s):

Elise Liu ◽

Léa Karpf ◽

Delphine Bohl

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Immune System ◽

Frontotemporal Dementia ◽

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Cell Types ◽

Induced Pluripotent ◽

Different Cell Types ◽

Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

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