Mechanisms of protein toxicity in neurodegenerative diseases

Chung

et al. 2019

Preprint

Self Cite

25Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated 26 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential 27 42 Staufen, may also be an important pathological feature of C9-ALS/FTD. 43 44 45 46 47 3 48 Author summary 49 Cytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common 50 pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia 51 (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded 52 (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-53 dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that 54 Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression 55 of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity 56 and further augmented by reduction in stau dosage, the gene encoding Staufen. When we 57 knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was 58 exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is 59 protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their 60 retinal degeneration and viability were largely rescued. Based on these data, we suggest that 61 nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that 62 reducing stau dosage is a promising therapeutic target.

Section: Discussionsupporting

confidence: 87%

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Chung

et al. 2019

Preprint

Self Cite

“…Cerebral amyloidopathy is a hallmark of neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) [1]. As a leading hypothesis in the pathogenesis of AD, the amyloid cascade hypothesis holds that amyloid-β (Aβ) aggregation in the central nervous system (CNS) is a primary etiology in AD and it is followed by neuroinflammation and neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

Honarpisheh

Reynolds

Conesa

et al. 2020

IJMS

Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

“…Huntington's disease, are characterized by the presence of intranuclear inclusions (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

The nucleolus functions as a phase-separated protein quality control compartment

Frottin

Schueder

Tiwary

et al. 2019

Science

401

337

The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation. Refolding and extraction of proteins from the nucleolus during recovery from stress was Hsp70-dependent. The capacity of the nucleolus to store misfolded proteins was limited, and prolonged stress led to a transition of the nucleolar matrix from liquid-like to solid, with loss of reversibility and dysfunction in quality control. Thus, we suggest that the nucleolus has chaperone-like properties and can promote nuclear protein maintenance under stress.