“…Accumulation of aggregates of abnormal proteins has indeed emerged as a common mechanism for most human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal dementias, and amyotrophic lateral sclerosis. All these diseases should propagate through the brain via prion-like intercellular induction of protein misfolding [ 136 , 137 ]. Neurons are peculiar cells in that they are postmitotic and cannot self-renew to clear abnormally folded/accumulated proteins; thus they accumulate protein folding errors, especially into aggregation-prone proteins, throughout their life-span [ 138 ].…”
Extracellular vesicles are involved in a great variety of physiological events occurring in the nervous system, such as cross talk among neurons and glial cells in synapse development and function, integrated neuronal plasticity, neuronal-glial metabolic exchanges, and synthesis and dynamic renewal of myelin. Many of these EV-mediated processes depend on the exchange of proteins, mRNAs, and noncoding RNAs, including miRNAs, which occurs among glial and neuronal cells. In addition, production and exchange of EVs can be modified under pathological conditions, such as brain cancer and neurodegeneration. Like other cancer cells, brain tumours can use EVs to secrete factors, which allow escaping from immune surveillance, and to transfer molecules into the surrounding cells, thus transforming their phenotype. Moreover, EVs can function as a way to discard material dangerous to cancer cells, such as differentiation-inducing proteins, and even drugs. Intriguingly, EVs seem to be also involved in spreading through the brain of aggregated proteins, such as prions and aggregated tau protein. Finally, EVs can carry useful biomarkers for the early diagnosis of diseases. Herein we summarize possible roles of EVs in brain physiological functions and discuss their involvement in the horizontal spreading, from cell to cell, of both cancer and neurodegenerative pathologies.
“…Accumulation of aggregates of abnormal proteins has indeed emerged as a common mechanism for most human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal dementias, and amyotrophic lateral sclerosis. All these diseases should propagate through the brain via prion-like intercellular induction of protein misfolding [ 136 , 137 ]. Neurons are peculiar cells in that they are postmitotic and cannot self-renew to clear abnormally folded/accumulated proteins; thus they accumulate protein folding errors, especially into aggregation-prone proteins, throughout their life-span [ 138 ].…”
Extracellular vesicles are involved in a great variety of physiological events occurring in the nervous system, such as cross talk among neurons and glial cells in synapse development and function, integrated neuronal plasticity, neuronal-glial metabolic exchanges, and synthesis and dynamic renewal of myelin. Many of these EV-mediated processes depend on the exchange of proteins, mRNAs, and noncoding RNAs, including miRNAs, which occurs among glial and neuronal cells. In addition, production and exchange of EVs can be modified under pathological conditions, such as brain cancer and neurodegeneration. Like other cancer cells, brain tumours can use EVs to secrete factors, which allow escaping from immune surveillance, and to transfer molecules into the surrounding cells, thus transforming their phenotype. Moreover, EVs can function as a way to discard material dangerous to cancer cells, such as differentiation-inducing proteins, and even drugs. Intriguingly, EVs seem to be also involved in spreading through the brain of aggregated proteins, such as prions and aggregated tau protein. Finally, EVs can carry useful biomarkers for the early diagnosis of diseases. Herein we summarize possible roles of EVs in brain physiological functions and discuss their involvement in the horizontal spreading, from cell to cell, of both cancer and neurodegenerative pathologies.
“…In seeded PrP C to PrP TSE conversion, the conformation of the PrP TSE template is typically reproduced with high fidelity. On this basis, phenotypically distinct prion agents that are made up of PrP with an identical amino acid and referred to as prion “types” or “strains” can exist and propagate in vivo in the form of different PrP conformers [ 14 , 45 , 94 ]. Fig.…”
Section: The Example Of Prions and Prion Diseasesmentioning
The misfolding and aggregation of endogenous proteins in the central nervous system is a neuropathological hallmark of Alzheimer’s disease (AD), Parkinson’s disease (PD), as well as prion diseases. A molecular mechanism referred to as “nucleation-dependent aggregation” is thought to underlie this neuropathological phenomenon. According to this concept, disease-associated protein particles act as nuclei, or seeds, that recruit cellular proteins and incorporate them, in a misfolded form, into their growing aggregate structure. Experimental studies have shown that the aggregation of the AD-associated proteins amyloid-β (Aβ) and tau, and of the PD-associated protein α-synuclein, can be stimulated in laboratory animal models by intracerebral (i.c.) injection of inocula containing aggregated species of the respective proteins. This has raised the question of whether AD or PD can be transmitted, like certain human prion diseases, between individuals by self-propagating protein particles potentially present on medical instruments or in blood or blood products. While the i.c. injection of inocula containing AD- or PD-associated protein aggregates was found to cause neuronal damage and clinical abnormalities (e.g., motor impairments) in some animal models, none of the studies published so far provided evidence for a transmission of severe or even fatal disease. In addition, available epidemiological data do not indicate a transmissibility of AD or PD between humans. The findings published so far on the effects of experimentally transmitted AD- or PD-associated protein seeds do not suggest specific precautionary measures in the context of hemotherapy, but call for vigilance in transfusion medicine and other medical areas.
“…Пептиды (начиная уже с шести аминокислот в них), первичная структура кото-рых соответствует части таковой участков бета-цепей указанного нормального белка, оказались достаточными для формирования в растворах амилоидных фибрилл [7]. Важно также то, что конформеры патогенных прионов (формы прионных белков, различающиеся по конфор-мационной структуре между собой) в процессе эволюции могут подвергаться отбору с образованием менее стабиль-ного и, следовательно, максимально быстро реплициру-ющегося типа [8].…”
Section: конформационные болезни вызванные мисфолдингом белкаunclassified
Благодаря уникальным структурным характеристи-кам белок стал выполнять в процессе эволюции все бо-лее важные функции в обеспечении жизнедеятельности клеток и организма в целом. Возможность включения в пептидную цепь аминокислот как с гидрофильными, так и с гидрофобными радикалами (в различных соот-ношениях) делает возможным интеграцию одних бел-ков в состав липопротеидных мембран и выполнение другими белками своих функций в водных растворах. При этом в различных условиях (даже при относительно небольших сдвигах параметров внутренней среды орга-низма) третичная и четвертичная структуры белков под-вергаются обратимым конформационным изменениям, что может существенно модифицировать их функции. Примеры такой регуляции функционирования белков известны при самых разных биохимических процессах, происходящих в клетке. Например, структура многих белков меняется в процессе фосфорилирования/де-фосфорилирования. В то же время чрезвычайное для молекулы белка отклонение условий среды может при-вести к существенному изменению ее конформации и выполняемой функции. Принципиальная возможность обратимости этого изменения ставится под вопрос. При этом клетка может адаптироваться к нарушению, например, изменением экспрессии гена недостающего белка. И, казалось бы, «проблема» решена: функция будет выполнена вновь синтезированным белком, а клетка вернется к состоянию гомеостаза. Однако воз-никают вопросы: что происходит с измененным белком; поглощается ли он фагоцитами (при внеклеточном расположении) или расщепляется протеазами клетки (при внутриклеточном); что может этому помешать? Как правило, альтерированные белки утилизируются. Описано по меньшей мере 3 основных пути деградации белка -протеосомальный, лизосомальный и фагосо-мальный. В каждом конкретном случае существенную роль играет убиквитин [1]
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