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Lipid alterations in Amyotrophic Lateral Sclerosis: from pathogenesis to potential therapies
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A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa fatal caracterizada pela degeneração progressiva dos neurónios motores. Apesar da sua etiologia permanecer pouco clara e do diagnóstico da doença enfrentar alguns desafios devido à heterogeneidade clínica da doença, os mecanismos subjacentes à ELA têm sido cada vez mais estudados, permitindo uma melhor compreensão dos mecanismos associados à patogénese da doença. Vários biomarcadores da doença têm sido identificados, como mutações genéticas dos genes C9orf72 e SOD, patologias relacionadas com a proteína TDP-43 ou variações nos níveis de neurofilamentos, facilitando a deteção da doença, a monitorização da sua progressão e a identificação de indivíduos susceptíveis, entre outras utilidades. O papel dos lípidos na doença, em particular no cérebro, é um tema emergente que tem vindo a ganhar relevância devido à variedade de processos que envolvem moléculas lipídicas e que aparecem perturbados na ELA, como a excitotoxicidade, o stress oxidativo, a neuroinflamação, a disfunção mitocondrial e as reacções imunitárias. As alterações no metabolismo dos lípidos, como a dislipidemia, são particularmente prevalentes nos doentes com ELA, mas nos últimos anos têm sido observadas outras alterações a nível lipídico. Os investigadores descreveram alterações nos níveis de esfingolípidos, fosfolípidos, ácidos gordos, lípidos esteróis e outras classes de lípidos quando compararam doentes com ELA com controlos saudáveis através da análise de amostras de sangue e de LCR. Além disso, foram descobertas mutações genéticas relacionadas com os esfingolípidos que têm sido amplamente associadas ao desenvolvimento da ELA juvenil. Também foram registadas alterações no metabolismo energético, especialmente hipermetabolismo, que foi identificado como uma caraterística muito prevalente da doença. As intervenções dietéticas têm sido estudadas ao longo dos anos, numa tentativa de encontrar formas de colmatar as necessidades energéticas acrescidas, evitando o desenvolvimento de mecanismos tóxicos como o stress oxidativo, fator importante na patogénese da ELA. Neste trabalho, será revisto o papel dos lípidos e das alterações lipídicas no desenvolvimento da ELA, de modo a identificar os principais processos celulares afetados pela doença e a forma como estes podem contribuir para a progressão da doença, juntamente com possíveis aplicações clínicas e áreas de investigação relacionadas com os lípidos na ELA.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration. Despite its etiology remaining unclear and the diagnosis of the disease facing some challenges due to the clinical heterogeneity of ALS features, the mechanisms underlying ALS have been increasingly studied, allowing for a better understanding of mechanisms associated with the pathogenesis of the disease. Several biomarkers of the disease have been identified, such as genetic mutations of C9orf72 and SOD genes, TDP-43 protein pathology or variations in neurofilament (NFs) levels, facilitating disease detection, monitoring its progression and identifying susceptible individuals, among other utilities. The role of lipids in the disease, particularly in the brain, is an emerging subject that has been gaining relevance due to the variety of processes involving lipid molecules that appear disrupted in ALS, such as excitotoxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction and immune reactions. Changes in lipid metabolism, such as dyslipidemia are particularly prevalent in ALS patients, but other alterations in lipid levels have been noted over the past years. Alterations in levels of sphingolipids, phospholipids, fatty acids, sterol lipids and other lipid classes have been described by researchers when comparing ALS patients with healthy controls by analyzing blood and CSF samples. Additionally, it were discovered genetic mutations related to sphingolipids that have been widely associated with the development of juvenile ALS. Changes in energy metabolism have also been reported, especially with hypermetabolism identified as a very prevalent feature of the disease. Dietary interventions have been studied over the years in an attempt to find ways to efficiently supply the body to fulfill the increased energy demands while preventing the development of toxic mechanisms such as oxidative stress, which is a major factor in ALS. In this work, it will be reviewed the role of lipids and lipid alterations on the development of ALS, in order to identify key cellular processes affected by the disease and how these can contribute to disease progression, along with possible clinical applications and areas of research related to lipids in ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration. Despite its etiology remaining unclear and the diagnosis of the disease facing some challenges due to the clinical heterogeneity of ALS features, the mechanisms underlying ALS have been increasingly studied, allowing for a better understanding of mechanisms associated with the pathogenesis of the disease. Several biomarkers of the disease have been identified, such as genetic mutations of C9orf72 and SOD genes, TDP-43 protein pathology or variations in neurofilament (NFs) levels, facilitating disease detection, monitoring its progression and identifying susceptible individuals, among other utilities. The role of lipids in the disease, particularly in the brain, is an emerging subject that has been gaining relevance due to the variety of processes involving lipid molecules that appear disrupted in ALS, such as excitotoxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction and immune reactions. Changes in lipid metabolism, such as dyslipidemia are particularly prevalent in ALS patients, but other alterations in lipid levels have been noted over the past years. Alterations in levels of sphingolipids, phospholipids, fatty acids, sterol lipids and other lipid classes have been described by researchers when comparing ALS patients with healthy controls by analyzing blood and CSF samples. Additionally, it were discovered genetic mutations related to sphingolipids that have been widely associated with the development of juvenile ALS. Changes in energy metabolism have also been reported, especially with hypermetabolism identified as a very prevalent feature of the disease. Dietary interventions have been studied over the years in an attempt to find ways to efficiently supply the body to fulfill the increased energy demands while preventing the development of toxic mechanisms such as oxidative stress, which is a major factor in ALS. In this work, it will be reviewed the role of lipids and lipid alterations on the development of ALS, in order to identify key cellular processes affected by the disease and how these can contribute to disease progression, along with possible clinical applications and areas of research related to lipids in ALS.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Amyotrophic lateral sclerosis (ALS) Lipid metabolism Neurodegenerative diseases Lipid alterations in ALS ALS biomarkers Mestrado integrado - 2024