Nature<\/a>, with Thinakaran serving as the co-senior author of an investigation done in collaboration with his former colleague Jubao Duan at the University of Chicago and Endeavor Health Research Institute.<\/p>\nThe paper shows how a variation in a particular gene, called PICALM, has a profound effect on the microglia. This change in the gene disrupts the microglia, heightening the likelihood of Alzheimer\u2019s developing, explained Ari Sudwarts, co-first author on the paper and a postdoctoral research scholar in the Morsani College of Medicine.<\/p>\n
\u201cWe made significant progress in understanding the functions of PICALM\u2014the third-most significant risk gene for late-onset Alzheimer\u2019s disease,\u201d Sudwarts says.<\/p>\n
\u201cWe found that a variant of PICALM affected the immune cells of the brain, reducing their ability to clear debris, and causing a buildup of cholesterol and lipids. Understanding the functions disrupted by a specific risk gene gives new targets for developing pharmaceuticals for patients who have this genetic variant.\u201d<\/p>\n
Thinakaran is working to learn more about PICALM and other common genetic variants that also have a profound impact, increasing the risk of developing the disease.<\/p>\n
\u201cThis is like gene mutations that cause cancer,\u201d he says. \u201cIf you have such a mutation, you\u2019re going to pass it on to your kids. There are only about three genes that have that kind of capability for Alzheimer\u2019s disease. All the others are called risk factors\u2014they don\u2019t cause the disease in all people, but they increase one\u2019s lifetime risk.\u201d<\/p>\n
He is fascinated by the challenge of figuring out how gene variants affect the disease, as well as how scientists can separate genetic effects from the lifestyle factors known to affect Alzheimer\u2019s risk.<\/p>\n
\u201cAn individual\u2019s risk in a lifetime becomes different, whether you exercise or not, whether you keep an active lifestyle or you\u2019re highly educated, and many other things,\u201d Thinakaran says. \u201cSo it becomes really difficult to narrow down and study genetic impacts.\u201d<\/p>\n
But over the last two decades, genetic methods have become more advanced and zeroed in on \u201chotspots\u201d in genes that increase one\u2019s lifetime risk. One such hotspot is the PICALM gene, which is associated with a risk of developing late-onset Alzheimer\u2019s.<\/p>\n
Much research has focused on the PICALM gene, as well as the PICALM protein it produces, over the past two decades, including that done at the University of Chicago and Endeavor Health Research Institute by Duan. Thinakaran collaborated with Duan on a research grant to further study PICALM-related risk factors and received federal funding in 2019, just after Thinakaran moved to USF.<\/p>\n
They oversaw a dual-lab study, involving cultured human-derived brain cells in petri dishes. Over time, this allowed them to gain a greater understanding of molecular changes in PICALM and the resulting increased risk of developing Alzheimer\u2019s. They learned that 30% of the population has a certain variant, or allele, of the PICALM gene. Called the \u201cminor allele\u201d of PICALM, it appears to protect people against Alzheimer\u2019s. But they wanted to understand the reason\u2014the mechanism\u2014for that.<\/p>\n
When they examined the data in cultured cells, they found the answer lay in the Pac-Men of the brain\u2014the microglia.<\/p>\n
\u201cDr. Duan found that the risk allele in PICALM only showed up in microglia,\u201d Thinakaran says. \u201cSo we said, let\u2019s introduce the change in the microglia, adding both the minor allele, which is protected from risk, and the major allele, which is not.\u201d<\/p>\n
As a result, they were able to find that the major allele reduces PICALM protein levels in the microglia. Having less PICALM protein damages organelles\u2014functional structures within a cell\u2014that degrade waste proteins called lysosomes. The less effective organelles disturb how proteins and lipids are managed in the cell, ultimately reducing the capacity for microglia to engulf protein material like amyloid and tau in the brain.<\/p>\n
\u201cThis creates these compact structures called lipid droplets that cause further havoc in a cell, and it impedes the microglia from doing its job,\u201d says Thinakaran. \u201cIt\u2019s extremely rare to have a story develop like this, and it took five years to unfold.\u201d<\/p>\n
The take-away message?<\/p>\n
\u201cMany risks are being identified in microglia,\u201d he says. \u201cAnd we are giving kind of a roadmap for one risk, and how the process results in lipid dysregulation and how the further accumulation of lipid droplets really starts to make the microglia ineffective. The knowledge we have gained adds one more piece to the Alzheimer\u2019s puzzle we are putting together.\u201d<\/p>\n
Source: University of South Florida<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"Share this Article You are free to share this article under the Attribution 4.0 International license. A type…\n","protected":false},"author":3,"featured_media":211146,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26],"tags":[10263,14400,10265,815,159,67,132,68],"class_list":{"0":"post-211145","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-alzheimers-disease","9":"tag-brains","10":"tag-genes","11":"tag-genetics","12":"tag-science","13":"tag-united-states","14":"tag-unitedstates","15":"tag-us"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@us\/115170823815022347","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/211145","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/comments?post=211145"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/211145\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media\/211146"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media?parent=211145"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/categories?post=211145"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/tags?post=211145"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}