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Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
Fratta P, Engel WK, McFerrin J, Davies KJ, Lin SW, Askanas V.2005. Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-beta precursor protein-overexpressing cultured human muscle fibers. Am J Pathol. 167:517-526.
Guillain-Barré syndrome after bortezomib therapy in a child with relapsed acute lymphoblastic leukemia
Published in Pediatric Hematology and Oncology, 2022
Valeria Ceolin, Rosita Cenna, Francesca Resente, Manuela Spadea, Franca Fagioli, Nicoletta Bertorello
Peripheral neuropathy (PN) has been described in patients receiving bortezomib, which is predominantly sensory. Symptoms include paresthesia, numbness in distal areas, particularly the lower limbs, burning sensations, dysesthesias, sensory loss, reduced proprioception, vibratory sensation, reduction of deep tendon reflexes and autonomic skin innervation. Neuropathic pain has also been described and happens more frequently than with other neurotoxic drugs.14 PN usually appears after a number of cycles of treatment and is associated with dose accumulation, but symptoms may also appear after the first few doses; recent studies28 did not find a clear linear correlation between the cumulative dose or dose intensity and the severity of polyneuropathy, indicating that certain patients developed a severe polyneuropathy following a relatively low dose of BZM. The pathophysiology of bortezomib induced neuropathy is not completely clear yet. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity.29
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
Some proteostasis modulators are reported to rescue F508del-CFTR by restoring autophagy that is defective in CF cells [89]. Autophagy is cytoprotective and normally removes damaged organelles and misfolded protein aggregates from specialized regions of the ER called aggresomes [90]. Its suppression in CF has been attributed to the generation of excess reactive oxygen species and subsequent SUMOylation and activation of the enzyme transglutaminase 2 (TMG2). TMG2 inhibits autophagy by crosslinking and sequestering beclin 1 (BECN1) and human vacuolar protein sorting protein 34 (hVps34), a class III phosphatidyl-inositol 3 kinase (PI3K) required to form the autophagosome [89]. Modulating proteostasis to stimulate autophagic flux in CF cells is proposed to have several beneficial effects including the restoration of F508del-CFTR trafficking, stabilization of CFTR at the cell surface by reducing plasma membrane levels of sequestrosome 1 (SQSTM1 also called p62), and enhancement of PI3K-dependent endosome recycling (reviewed by [91].
When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies
Published in Expert Review of Proteomics, 2018
Julie A. Reisz, Alexander S. Barrett, Travis Nemkov, Kirk C. Hansen, Angelo D’Alessandro
Altered cellular proteostasis underlies the pathophysiology of many NDDs such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, which disproportionately affect elderly populations. The physiological signature of Down syndrome (DS) is also marked by imbalanced proteostasis and accelerated aging processes. These diseases have in common a sustained stimulation of microglia (reviewed in [108]), the innate immune system in the brain, along with increased levels of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), and interleukin 6 (IL-6). Additionally, NDDs are marked by propensities for protein covalent cross-links mediated by transglutaminase [109] and large intracellular concentrations of proteins with unfolded regions; in some cases, these outcomes are a result of familial or sporadic genetic mutations. Disordered, unfolded protein regions are typically handled by cellular chaperones, but have a tendency in these disease states to overwhelm the capacity of the chaperone system, leading to a ‘gain of function’ where nascent exposed regions bind indiscriminately to proteins, organelles, and biomolecules with similar polarities, ultimately leading to the formation of aggregates or amyloids. Protein aggregates, sometimes termed aggresomes, obstruct the normal function of the organelle in which they reside and routinely lead to cell death. The formation of amyloids and aggresomes in neurons disrupt synaptic transmission and cell metabolism; subsequent neuronal death underlies brain degeneration and dementia.