Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many of its physiological functions are only partially understood. α-syn accumulation is associated with Parkinson's ...disease, dementia with Lewy bodies, and multiple system atrophy as well as other synucleinopathies; however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what is known about α-syn function and pathophysiological changes in different cellular structures and organelles, including what is known about its behavior as a prion-like protein. We summarize current knowledge of α-syn and its pathological forms, covering its effect on each organelle, including aggregation and toxicity in different model systems, with special interest on the mitochondria due to its relevance during the apoptotic process of dopaminergic neurons. Moreover, we explore the effect that α-syn exerts by interacting with chromatin remodeling proteins that add or remove histone marks, up-regulate its own expression, and resume the impairment that α-syn induces in vesicular traffic by interacting with the endoplasmic reticulum. We then recapitulate the events that lead to Golgi apparatus fragmentation, caused by the presence of α-syn. Finally, we report the recent findings about the accumulation of α-syn, indirectly produced by the endolysosomal system. In conclusion, many important steps into the understanding of α-syn have been made using
and
models; however, the time is right to start integrating observational studies with mechanistic models of α-syn interactions, in order to look at a more complete picture of the pathophysiological processes underlying α-synucleinopathies.
Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several ...disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.
IntroductionDeath following surgical procedures is a global health problem, accounting for 4.2 million deaths annually within the first 30 postoperative days. The fourth indicator of The Lancet ...Commission on Global Surgery is essential as it seeks to standardise postoperative mortality. Consequently, it helps identify the strengths and weaknesses of each country’s healthcare system. Accurate information on this indicator is not available in Colombia, limiting the possibility of interventions applied to our population. We aim to describe the in-hospital perioperative mortality of the surgical procedures performed in Colombia. The data obtained will help formulate public policies, improving the quality of the surgical departments.Methods and analysisAn observational, analytical, multicentre prospective cohort study will be conducted throughout Colombia. Patients over 18 years of age who have undergone a surgical procedure, excluding radiological/endoscopic procedures, will be included. A sample size of 1353 patients has been projected to achieve significance in our primary objective; however, convenience sampling will be used, as we aim to include all possible patients. Data collection will be carried out prospectively for 1 week. Follow-up will continue until hospital discharge, death or a maximum of 30 inpatient days. The primary outcome is perioperative mortality. A descriptive analysis of the data will be performed, along with a case mix analysis of mortality by procedure-related, patient-related and hospital-related conditionsEthics and disseminationThe Fundación Cardioinfantil-Instituto de Cardiología Ethics Committee approved this study (No. 41–2021). The results are planned to be disseminated in three scenarios: the submission of an article for publication in a high-impact scientific journal and presentations at the Colombian Surgical Forum and the Congress of the American College of Surgeons.Trial registration numberNCT05147623.
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