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Disfunção lisossomal: uma ligação-chave para compreender a patogénese da Doença de Parkinson
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A Doença de Parkinson é a segunda doença neurodegenerativa mais comum mundialmente, afetando cerca de 1% da população com mais de 60 anos. Caracterizase pela presença de agregados anómalos da proteína alfa-sinucleína no tecido neuronal, resultando na formação de corpos de Lewy e na morte celular de neurónios dopaminérgicos na substancia nigra. Atualmente, é uma doença sem cura, em que os tratamentos visam apenas aliviar os sintomas.
O sistema autofágico endo-lisossomal é uma rede interligada, com o lisossoma como ponto central, responsável pela degradação e reciclagem de macromoléculas. Os lisossomas contêm enzimas hidrolíticas que degradam materiais intracelulares e extracelulares entregues por autofagia e endocitose, mantendo a homeostase celular.
O envelhecimento causa uma diminuição progressiva da capacidade de processamento lisossomal, afetando várias doenças neurodegenerativas, nomeadamente a Doença de Parkinson, Alzheimer, Esclerose Lateral Amiotrófica e Demência Frontotemporal. Na Doença de Parkinson, a degradação da alfa-sinucleína pelo sistema autofágico endo lisossomal, mediada principalmente pelos lisossomas, é fundamental para manter os níveis normais desta proteína e impedir a sua toxicidade. A disfunção da degradação lisossomal e da maquinaria autofágica pode, assim, levar à acumulação patológica desta proteína nos neurónios.
Estudos genéticos revelaram diversos genes e proteínas lisossomais ligados à Doença de Parkinson, em destaque o gene GBA1, que codifica a enzima βglucocerebrosidase, cuja atividade reduzida leva à acumulação de alfa-sinucleína. Mutações no gene ATP13A2 também provocam falha lisossomal e aumento de alfasinucleína. Outros genes e proteínas importantes incluem o gene TMEM175, que regula o pH lisossomal e influencia a degradação de alfa sinucleína, e o TFEB, que promove a eliminação de oligómeros desta proteína.
As semelhanças nas vias patogénicas das doenças de armazenamento lisossomal e doenças neurodegenerativas revelam alvos potenciais para tratamentos inovadores, que oferecem novas perspetivas para abordar a patologia da Doença de Parkinson, ainda que muitos destes métodos estejam em fase experimental e requeiram mais estudos clínicos.
Parkinson's disease is the second most common neurodegenerative disease worldwide, affecting around 1% of the population over 60. It is characterised by the presence of abnormal aggregates of the protein alpha-synuclein in neuronal tissue, resulting in the formation of Lewy bodies and the cell death of dopaminergic neurons in the substantia nigra. It is currently a disease without a cure, with treatments aimed only at relieving symptoms. The autophagic endo-lysosomal system is an interconnected network, with the lysosome at its centre, responsible for the degradation and recycling of macromolecules. Lysosomes contain hydrolytic enzymes that degrade intracellular and extracellular materials delivered by autophagy and endocytosis, maintaining cellular homeostasis. Ageing causes a progressive decrease in lysosomal processing capacity, affecting several neurodegenerative diseases, namely Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. In Parkinson's disease, the degradation of alpha-synuclein by the autophagic endolysosomal system, mediated mainly by lysosomes, is essential for maintaining normal levels of this protein and preventing its toxicity. Dysfunction of lysosomal degradation and the autophagic machinery can therefore lead to the pathological accumulation of this protein in neurons. Genetic studies have revealed several genes and lysosomal proteins linked to Parkinson's disease, in particular the GBA1 gene, which encodes the βglucocerebrosidase enzyme, whose reduced activity leads to the accumulation of alpha-synuclein. Mutations in the ATP13A2 gene also cause lysosomal failure and an increase in alpha-synuclein. Other important genes and proteins include the TMEM175 gene, which regulates lysosomal pH and influences the degradation of alpha-synuclein, and TFEB, which promotes the elimination of oligomers of this protein. The similarities in the pathogenic pathways of lysosomal storage diseases and neurodegenerative diseases reveal potential targets for innovative treatments, which offer new perspectives for addressing the pathology of Parkinson's disease, although many of these methods are still in the experimental phase and require further clinical studies.
Parkinson's disease is the second most common neurodegenerative disease worldwide, affecting around 1% of the population over 60. It is characterised by the presence of abnormal aggregates of the protein alpha-synuclein in neuronal tissue, resulting in the formation of Lewy bodies and the cell death of dopaminergic neurons in the substantia nigra. It is currently a disease without a cure, with treatments aimed only at relieving symptoms. The autophagic endo-lysosomal system is an interconnected network, with the lysosome at its centre, responsible for the degradation and recycling of macromolecules. Lysosomes contain hydrolytic enzymes that degrade intracellular and extracellular materials delivered by autophagy and endocytosis, maintaining cellular homeostasis. Ageing causes a progressive decrease in lysosomal processing capacity, affecting several neurodegenerative diseases, namely Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. In Parkinson's disease, the degradation of alpha-synuclein by the autophagic endolysosomal system, mediated mainly by lysosomes, is essential for maintaining normal levels of this protein and preventing its toxicity. Dysfunction of lysosomal degradation and the autophagic machinery can therefore lead to the pathological accumulation of this protein in neurons. Genetic studies have revealed several genes and lysosomal proteins linked to Parkinson's disease, in particular the GBA1 gene, which encodes the βglucocerebrosidase enzyme, whose reduced activity leads to the accumulation of alpha-synuclein. Mutations in the ATP13A2 gene also cause lysosomal failure and an increase in alpha-synuclein. Other important genes and proteins include the TMEM175 gene, which regulates lysosomal pH and influences the degradation of alpha-synuclein, and TFEB, which promotes the elimination of oligomers of this protein. The similarities in the pathogenic pathways of lysosomal storage diseases and neurodegenerative diseases reveal potential targets for innovative treatments, which offer new perspectives for addressing the pathology of Parkinson's disease, although many of these methods are still in the experimental phase and require further clinical studies.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Doença de Parkinson Lisossomas Neurodegeneração α-sinucleína Autofagia Mestrado Integrado - 2024