{"id":29934,"date":"2024-08-30T14:44:45","date_gmt":"2024-08-30T18:44:45","guid":{"rendered":"https:\/\/biology.mit.edu\/?p=29934"},"modified":"2024-08-30T14:44:45","modified_gmt":"2024-08-30T18:44:45","slug":"whitehead-institute-researchers-uncover-a-new-clue-toward-understanding-the-molecular-basis-of-parkinsons-disease","status":"publish","type":"post","link":"https:\/\/biology.mit.edu\/whitehead-institute-researchers-uncover-a-new-clue-toward-understanding-the-molecular-basis-of-parkinsons-disease\/","title":{"rendered":"Whitehead Institute researchers uncover a new clue toward understanding the molecular basis of Parkinson\u2019s disease"},"content":{"rendered":"<div class=\"article-layout-section__region article-layout-section__region--left col-m-2 col-l-3\">\n<div class=\"article-share article-share--vertical block block-better-social-sharing-buttons block-social-sharing-buttons-block\">\n<div class=\"social-sharing-buttons is-affixed\">\n<div class=\"inner-wrapper-sticky\">\n<div class=\"social-sharing-buttons__popup\">Copied to clipboard<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"article-layout-section__region article-layout-section__region--center col-m-8 col-l-6\">\n<div class=\"block block-layout-builder block-field-blocknodenewsitemfield-content block-field\">\n<div class=\"field field--name-field-content field--type-entity-reference-revisions field--label-hidden field__items\">\n<div class=\"field__item\">\n<div class=\"paragraph paragraph--type--text paragraph--view-mode--default\">\n<div class=\"clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item\">\n<p>Dopamine is more than the \u201crush molecule\u201d. This chemical messenger, produced by neurons in the midbrain, acts as a traffic controller that regulates the flow of electrical signals between neurons, assisting with brain functions like cognition, attention, movement, and behavior. But, in instances of Parkinson\u2019s disease (PD), a progressive brain disorder, dopamine-producing neurons begin to die at an unprecedented rate, leading to dwindling levels of this vital chemical and impaired neural communication.<\/p>\n<p>The lab of Whitehead Institute\u2019s Founding Member Rudolf Jaenisch studies genetic and epigenetic factors \u2014 changes in gene expression that control which genes are turned on and off, and to what extent, without altering the DNA sequence itself \u2014 underlying neurological disorders like PD, Alzheimer\u2019s disease, and Rett Syndrome. Their work aims to uncover the mechanisms that go awry in the brain, which may inform the development of new therapies that can halt or even reverse the progression of these conditions.<\/p>\n<p>In their latest work, Jaenisch and former postdoctoral associate Marine Krzisch examine how a mutation in the gene that encodes for alpha-synuclein, a protein regulating the release of dopamine, affects the resident immune cells of the brain called microglia. The researchers\u2019 detailed findings,\u00a0<a class=\"ext\" href=\"https:\/\/www.biologicalpsychiatryjournal.com\/article\/S0006-3223(24)01459-8\/fulltext\" target=\"_blank\" rel=\"noopener noreferrer\" data-extlink=\"\">published in the journal\u00a0<em>Biological Psychiatry<\/em><\/a>\u00a0on August 29, reveal that the mutation renders microglia extremely sensitive, worsening the problem of inflammation in the brain and potentially exacerbating damage to neurons in Parkinson\u2019s disease.<\/p>\n<p>\u201cIn fact, even when these mutant microglia are transplanted into a healthy, young brain, they have heightened activation upon stimulation, and low levels of the protective antioxidant catalase,\u201d Krzisch says. \u201cThis tells us that in Familial Parkinson\u2019s disease, which is due to genetic mutations, these microglia may be playing an important role in neuron degeneration.\u201d<\/p>\n<h2>When nature\u2019s origami falters<\/h2>\n<p>The human body is home to tens of thousands of unique proteins, each essential for processes sustaining life. These proteins are composed of linear chains of smaller building blocks called amino acids that are linked together in a specific sequence. For the proteins to perform their functions, the amino acid chains must crumple, rotate, and twist into stable three-dimensional structures. The stakes are high \u2014 just as precise folds and creases are crucial to the art of origami, even minor errors in the protein folding process can result in dysfunctional proteins that contribute to disease.<\/p>\n<p>To date, scientists have identified over 20 causative genes in which mutations can result in Familial Parkinson\u2019s disease, a rare, genetically inherited form of PD affecting individuals under or around the age of 50. Among them is\u00a0<em>SNCA<\/em>, which encodes for alpha-synuclein, a small protein abundant in dopamine-producing neurons.<\/p>\n<p>The A53T mutation in\u00a0<em>SNCA<\/em>\u00a0promotes the formation of dysfunctional alpha-synuclein proteins that clump together \u2014 almost like a ball of yarn \u2014 within dopamine-producing neurons. The accumulation of these protein clumps, also known as Lewy bodies, triggers inflammatory signaling in the brain, eventually killing the affected neurons. However, prior research has also shown that the A53T mutation accelerates the progression of PD, or the rate at which neurons die, although the full molecular mechanisms underlying this process are not yet fully understood.<\/p>\n<p>To uncover pathways involved in this progression, researchers in the Jaenisch Lab turned their attention to star-shaped patrollers called microglia that protect the brain from foreign invaders and respond to injuries, including protein aggregates within neurons. This immune response includes activated microglia trying to clear out Lewy bodies by digesting them, recruiting additional immune cells to the site of neurons with protein aggregates, and even killing off diseased neurons to limit damage to the brain.<\/p>\n<p>But these friends can quickly turn to foes. Over-activated microglia can also degrade healthy neurons in the brain, prompting Jaenisch, Krzisch, and colleagues to investigate if excessive microglia activation is one pathway that contributes to progression in PD.<\/p>\n<h2>Microglia go rogue<\/h2>\n<p>To explore how the A53T mutation in the\u00a0<em>SNCA<\/em>\u00a0gene affects microglia function in PD, scientists at the Jaenisch Lab began by growing human myeloid precursors \u2014 the cells that eventually develop into microglia \u2014 in lab culture and transplanting them into the brains of immune-deprived mice.<\/p>\n<p>Given the complexity of the brain, it\u2019s common for researchers to study brain cells in the Petri dish. \u201cBut in cell cultures, microglia do not have the same morphology [form] as in the brain, show signs of chronic activation, and they don&#8217;t survive for a very long time,\u201d says Krzisch. \u201cWhen we transplant them in mice, the precursors differentiate into microglia that look and function like those in the human brain, and survive for the mouse\u2019s lifespan.\u201d<\/p>\n<p>Using this method, the researchers compared the gene expression profiles of A53T-mutant microglia with those that did not carry the mutation, revealing differences in pathways linked to inflammation, microglia activation, and DNA repair. Additionally, when A53T-mutant microglia were exposed to an immune activator called lipopolysaccharide, they exhibited a heightened inflammatory response compared to non-mutant microglia.<\/p>\n<p>In fact, even in non-inflammatory conditions, A53T-mutant microglia had decreased expression of catalase, an enzyme that helps break down harmful reactive oxygen species produced in response to protein aggregates in PD.<\/p>\n<p>Understanding the molecular basis of progression in PD is challenging, which explains why there are currently no drugs to alter the disease\u2019s course. With these findings in hand, researchers at the Jaenisch Lab are now eager to explore how factors like aging also influence microglia function and contribute to an increased rate of progression in PD.<\/p>\n<p>\u201cOveractivation of microglia isn\u2019t the only cause of neuron death in Parkinson\u2019s,\u201d says Jaenisch. \u201cBut if we can decrease their activation, it will help us get to the point where we can slow down or actually stop the disease.\u201d<\/p>\n<p>&nbsp;<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Copied to clipboard Dopamine is more than the \u201crush molecule\u201d. This chemical messenger, produced by neurons in the midbrain, acts as a traffic controller that regulates the flow of electrical signals between neurons, assisting with brain functions like cognition, attention, movement, and behavior. But, in instances of Parkinson\u2019s disease (PD), a progressive brain disorder, dopamine-producing [&hellip;]<\/p>\n","protected":false},"author":1783,"featured_media":29935,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[6212,6221],"tags":[],"class_list":["post-29934","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news-briefs","category-whitehead-institute","placement-placement-homepage","research-area-human-disease","research-area-neurobiology","research-area-stem-cell-and-developmental-biology"],"acf":[],"yoast_head":"\n<title>Whitehead Institute researchers uncover a new clue toward understanding the molecular basis of Parkinson\u2019s disease - MIT Department of Biology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/biology.mit.edu\/whitehead-institute-researchers-uncover-a-new-clue-toward-understanding-the-molecular-basis-of-parkinsons-disease\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Whitehead Institute researchers uncover a new clue toward understanding the molecular basis of Parkinson\u2019s disease\" \/>\n<meta property=\"og:description\" content=\"Copied to clipboard Dopamine is more than the \u201crush molecule\u201d. This chemical messenger, produced by neurons in the midbrain, acts as a traffic controller that regulates the flow of electrical signals between neurons, assisting with brain functions like cognition, attention, movement, and behavior. 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