A review on protein misfolding, aggregation and strategies to prevent related ailments

Shamsi, Tooba Naz; Athar, Teeba; Parveen, Rabea; Fatima, Sadaf

doi:10.1016/j.ijbiomac.2017.07.116

Cited by 39 publications

(26 citation statements)

References 116 publications

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“…One of these mutations mapped to the previously characterized sallamus (sls) locus and encodes for the large muscle protein Titin, validating the functionality of our screening approach in identifying mutants that are defective in muscle structure and/or function. Deficiency (Df) mapping of the mutation in Fig 1B, originally designated l (3)17289, narrowed the region down to nine protein encoding genes within Df(3R) BCS479 (S1 Fig). Sequencing of messenger RNAs (mRNA) isolated from l (3)17289 homozygous mutants revealed a C!T transition resulting in a premature stop codon (AA829) in the uncharacterized gene CG43143 (hereafter referred to as NUAK) (S1 Fig).…”

Section: Nuak Mutants (Nuak-/-) Exhibit a Degenerative Muscle Phenotypementioning

confidence: 99%

“…Deficiency (Df) mapping of the mutation in Fig 1B, originally designated l (3)17289, narrowed the region down to nine protein encoding genes within Df(3R) BCS479 (S1 Fig). Sequencing of messenger RNAs (mRNA) isolated from l (3)17289 homozygous mutants revealed a C!T transition resulting in a premature stop codon (AA829) in the uncharacterized gene CG43143 (hereafter referred to as NUAK) (S1 Fig). Gross level examination of third larval instar (L3) fillets revealed a dramatic loss of tissue integrity in muscles homozygous for the l(3)17289 alelle (NUAK-/-), primarily characterized by thinning or detached muscles (Fig 1C and 1D).…”

Section: Nuak Mutants (Nuak-/-) Exhibit a Degenerative Muscle Phenotypementioning

confidence: 99%

“…Drosophila stocks were obtained from the Bloomington (BL) Drosophila Stock Center (BDSC), the Vienna Drosophila Resource Center (VDRC), or the Kyoto Drosophila Genetic Resource Center (DGRC). The NUAK l (3)17289 allele was isolated in an EMS screen [36] and analyzed over the deficiency stock Df(3R)BSC479 (BL24983). Other mutant alleles used in experiments were stv 1 /TM6, Tb (a gift from Jörg Höhfeld) [11] and stv 00543 /TM3, Sb (BL11501).…”

Section: Drosophila Stocks and Growth Conditionsmentioning

confidence: 99%

“…The progeny of each cross were screened for pupal lethality and extended pupal case morphology. The l (3)17289 allele failed to complement Df(3R)ED5474 (BL9082). Verification with additional overlapping Df stocks narrowed down the cytological region to 86A3 to 86B1.…”

Section: Mapping and Sequencing Of Nuak Mutantsmentioning

confidence: 99%

“…Proteins must fold into an intrinsic three dimensional structure to perform distinct cellular functions. Denatured or misfolded proteins can be refolded by chaperones or are subject to degradation by the ubiquitin-proteasome system (UPS) and/or the autophagosome-lysosome pathway (ALP) [1][2][3]. The accumulation of misfolded proteins upon genetic mutation or decreased chaperone function causes protein aggregates that are not effectively cleared by the UPS or the ALP.…”

Section: Introductionmentioning

confidence: 99%

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Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover

et al. 2020

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The inability to remove protein aggregates in post-mitotic cells such as muscles or neurons is a cellular hallmark of aging cells and is a key factor in the initiation and progression of protein misfolding diseases. While protein aggregate disorders share common features, the molecular level events that culminate in abnormal protein accumulation cannot be explained by a single mechanism. Here we show that loss of the serine/threonine kinase NUAK causes cellular degeneration resulting from the incomplete clearance of protein aggregates in Drosophila larval muscles. In NUAK mutant muscles, regions that lack the myofibrillar proteins F-actin and Myosin heavy chain (MHC) instead contain damaged organelles and the accumulation of select proteins, including Filamin (Fil) and CryAB. NUAK biochemically and genetically interacts with Drosophila Starvin (Stv), the ortholog of mammalian Bcl-2-associated athanogene 3 (BAG3). Consistent with a known role for the co-chaperone BAG3 and the Heat shock cognate 71 kDa (HSC70)/HSPA8 ATPase in the autophagic clearance of proteins, RNA interference (RNAi) of Drosophila Stv, Hsc70-4, or autophagy-related 8a (Atg8a) all exhibit muscle degeneration and muscle contraction defects that phenocopy NUAK mutants. We further demonstrate that Fil is a target of NUAK kinase activity and abnormally accumulates upon loss of the BAG3-Hsc70-4 complex. In addition, Ubiquitin (Ub), ref(2)p/p62, and Atg8a are increased in regions of protein aggregation, consistent with a block in autophagy upon loss of NUAK. Collectively, our results establish a novel role for NUAK with the Stv-Hsc70-4 complex in the autophagic clearance of proteins that may eventually lead to treatment options for protein aggregate diseases.

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Section: Nuak Mutants (Nuak-/-) Exhibit a Degenerative Muscle Phenotypementioning

confidence: 99%

Section: Nuak Mutants (Nuak-/-) Exhibit a Degenerative Muscle Phenotypementioning

confidence: 99%

Section: Drosophila Stocks and Growth Conditionsmentioning

confidence: 99%

Section: Mapping and Sequencing Of Nuak Mutantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover

et al. 2020

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The etiology of long‐term stable mild cognitive impairment

Sharma

Callahan

2020

Alzheimer's & Dementia

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Background Of those diagnosed with mild cognitive impairment (MCI), 5‐10% convert annually to dementia (Mitchell & Shiri‐Feshki, 2009). However, 5‐30% can remain cognitively stable (sMCI) for up to 10 years (Alves et al., 2018), suggesting a non‐neurodegenerative etiology in these patients. This study aims to examine the etiological underpinnings of those who remain cognitively stable versus those who decline over time. Method Participants from the National Alzheimer’s Coordinating Center were selected if they were nondemented at baseline, had available clinical data ≥5 years following baseline, and had available autopsy data <1.5 years following last visit. They were defined as stable normal controls (sNC; n = 106) or sMCI (n = 28) if cognitive status was unchanged between first and last visit (≥5 years later); declined normal controls (dNC; n = 128) if cognitive status at first visit was normal and MCI or demented by last visit; or declined MCI (dMCI; n = 139) if cognitive status was MCI at first visit and demented by last visit. Neuropathological features were dichotomized to reflect clinically significant levels (≥moderate neuritic plaque density; Braak neurofibrillary degeneration stage ≥4; Thal amyloid plaque phase ≥3; any Lewy bodies; ≥1 large arterial infarct; ≥1 lacune; ≥1 microbleed; ≥1 hemorrhage). Baseline psychiatric symptoms were quantified using the Geriatric Depression Scale (GDS; ≥6 considered clinically significant) and the Neuropsychiatric Inventory Questionnaire (NPI‐Q; grouped into ‘mood’, ‘agitation’ and ‘psychosis’ factors based on previous factor analysis: Aalten et al., 2003, Siafarikas et al., 2018). The groups were compared on frequencies of neuropathological features at autopsy and baseline psychiatric symptoms using chi‐square (χ 2). Result Demographics are presented in Table 1, with main analysis results in Table 2. Relative to other groups, sMCI had significantly fewer amyloid plaques (χ 2 = 44.2, p < 0.001) and more microinfarcts (χ 2 = 9.9, p = .019). GDS and NPI‐Q showed no significant relationship with sMCI. Conclusion Previous research indicates microinfarcts are independent of neurodegenerative disease (Launer et al., 2011). In line with this, our results suggest that sMCI may be caused by microinfarcts, rather than frank neurodegenerative disease. This study was limited as only neuropsychiatric symptoms were reported, and future studies should examine sMCI in relation to diagnosed psychiatric disorders.

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