Mutant huntingtin is present in neuronal grafts in huntington disease patients

Cicchetti, Francesca; Lacroix, Steve; Cisbani, Giulia; Vallières, Nicolas; Saint-Pierre, Martine; St‐Amour, Isabelle; Tolouei, R.; Skepper, Jeremy N.; Hauser, Robert A.; Mantovani, Diego; Barker, Roger A.; Freeman, Thomas B.

doi:10.1002/ana.24174

Cited by 168 publications

(143 citation statements)

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“…Additionally, in patients with HD, mutant huntingtin aggregates accumulate in brain endothelial cells, perivascular macrophages, vascular smooth muscle cells, and vascular basal lamina 60 , and in genetically unrelated fetal neural allografts in the brains of patients with advanced HD 205 . These data suggest that the cerebral vasculature and immune system contribute to the spread of mutant huntingtin as well as the ability of non-neuronal cells including vascular cells to contribute to spreading of HTT mutant.…”

Section: Postmortem Evidence Of Bbb Disruptionmentioning

confidence: 99%

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

2018

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The blood–brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts, and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation, and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells, and microbial pathogens, and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain, post-mortem tissue and biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery, and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting BBB are presented.

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Section: Postmortem Evidence Of Bbb Disruptionmentioning

confidence: 99%

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

2018

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“…Indeed, several studies suggested that most aggregation-prone proteins linked to neurodegenerative diseases (Prusiner, 2012), including a-syn (Desplats et al, 2009;Lee et al, 2010b;Luk et al, 2009), huntingtin (Cicchetti et al, 2014), tau (Clavaguera et al, 2009), superoxide dismutase 1 (Grad et al, 2011;Munch et al, 2011) or b-amyloid (Meyer-Luehmann et al, 2006), can be transferred from cell-to-cell in both in vitro and in vivo experiments. In this section, we will review evidence pointing to the spreading-like properties of the various causative proteins of these diseases (Ab and tau for AD, and a-syn for PD).…”

Section: Disease-related Protein Spreading In Alzheimer's and Parkinsmentioning

confidence: 99%

Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies

Bourdenx

Koulakiotis

Sanoudou

et al. 2017

Progress in Neurobiology

142

117

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“…One approach to correcting this deficit is to transplant new neuronal tissue, a strategy that has shown some promise in animal models of the disease (Dunnett et al 1998). Early human studies have shown potential for graft survival, although a recent long-term follow-up study was less encouraging, and mutant huntingtin was found in transplanted tissue (Barker et al 2013;Cicchetti et al 2014). The variable results in terms of graft survival, safety, and outcome may reflect differences in protocol and procedure, which may lead to more successful trials now that a proof of principle has been established.…”

Section: Transplantationmentioning

confidence: 99%