{"id":63285,"date":"2025-08-12T06:07:07","date_gmt":"2025-08-12T06:07:07","guid":{"rendered":"https:\/\/www.newsbeep.com\/ca\/63285\/"},"modified":"2025-08-12T06:07:07","modified_gmt":"2025-08-12T06:07:07","slug":"a-genetic-mutation-linked-to-als-and-dementia-miswires-gene-expression","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/ca\/63285\/","title":{"rendered":"A Genetic Mutation Linked to ALS and Dementia Miswires Gene Expression"},"content":{"rendered":"

Newswise \u2014 It may be time to rethink certain genetic mutations associated with two devastating neurodegenerative disorders\u2014amyotrophic lateral sclerosis<\/a> (ALS) and frontotemporal dementia (FTD)\u2014according to a new Nature Neuroscience<\/a> study from researchers at Yale School of Medicine (YSM).<\/p>\n

ALS is a devastating neurological disease marked by the progressive degeneration of nerve cells in the brain and spinal cord. In some cases, ALS can be accompanied by FTD, a type of dementia that causes damage to the temporal and frontal lobes of the brain, resulting in changes to behavior, personality, and speech.<\/p>\n

While the cause for most ALS and FTD cases is still unknown, genetic mutations play a significant role, particularly in cases where there\u2019s a family history of these disorders. The most common genetic mutation in European and North American populations with these conditions lies within the C9orf72 gene.<\/p>\n

If we can identify these regulators, they could become potential targets for manipulating and reversing these abnormal events.<\/p>\n

Junjie Guo, PhD<\/p>\n

Interestingly, unlike most genetic mutations that cause human diseases, the C9orf72 mutation is located within what is called an intron of the gene. Introns are typically considered \u201csilent\u201d regions within most genes in our DNA. While both introns and their counterparts known as exons are initially transcribed into RNA, introns are later removed during a process called splicing, leaving only the exons to form the mature messenger RNA (mRNA) transcripts that carry instructions to assemble proteins.<\/p>\n

Therefore, introns are not expected to participate in producing proteins. But an apparent exception lies in C9orf72.<\/p>\n

Within the first intron of this gene, a mutation causes a short DNA sequence to repeat itself hundreds of times. According to the typical understanding of introns, these repeats, when transcribed into RNA, should be removed by splicing and should not lead to protein production. But recent studies have shown that these repeats do in fact produce toxic repeat proteins that can accumulate in the brain and spinal cord, potentially contributing to neurodegeneration.<\/p>\n

\u201cThese repeat proteins can interfere with a wide range of cell functions,\u201d explains Suzhou Yang, a PhD student in Yale\u2019s Interdepartmental Neuroscience Program and lead author of the study. \u201cBut it has been a mystery how an intronic sequence, which is usually cut out and degraded, can be translated into these toxic proteins.\u201d<\/p>\n

But now, Yang and Junjie Guo, PhD, associate professor of neuroscience at YSM and senior author of the study, have uncovered a crucial mechanism that helps solve this mystery. Their study, published on Aug. 11, has the potential to expand therapeutic possibilities for ALS and FTD, and provide insights into other diseases associated with similar mutations.<\/p>\n

Aberrant splicing turns introns into exons<\/p>\n

A major challenge in understanding the biology of the C9orf72 mutation has been the extremely low abundance of the mutant RNA molecules in patient cells\u2014there\u2019s just not a lot of it available to work with. To overcome this challenge, Yang and Guo developed a novel method to isolate and characterize these rare RNA molecules.<\/p>\n

This allowed them to discover an important piece of the puzzle as to why the repeats were not removed through splicing\u2014the intron in question actually becomes part of an exon.<\/p>\n

Normally, the cell\u2019s splicing machinery precisely removes introns from RNA and pieces back together the neighboring exons. But in this case, the presence of the repeat sequences somehow misdirects the splicing machinery, causing a portion of the intron, including the repeats, to be retained in the mature RNA.<\/p>\n

\u201cPart of the reason why it took us so long to find this is perhaps our static way of thinking about the genome and gene expression,\u201d says Guo. \u201cBut once we saw the RNA sequence, this abnormal process immediately jumped out to us.\u201d<\/p>\n

They found that certain previously known splicing factors play a role in shaping the aberrant splicing patterns. Furthermore, collaborating with their colleagues from the iPSC-Neurocore in Yale\u2019s Department of Neuroscience, they observed that different cell types carrying the same mutation, such as skin fibroblasts and motor neurons, exhibit different splicing outcomes.<\/p>\n

Further research is still needed to fully understand how the repeat sequences cause C9orf72 aberrant splicing.<\/p>\n

\u201cIt is most likely that there are additional cell-type-specific splicing regulators that determine the incorrect splice sites,\u201d Guo explains. \u201cIf we can identify these regulators, they could become potential targets for manipulating and reversing these abnormal events.\u201d<\/p>\n

Expanding therapeutic possibilities for ALS and FTD<\/p>\n

With approximately 10% of ALS cases caused by this C9orf72 mutation, Yang and Guo\u2019s results indicate new possibilities for ALS and FTD treatment. Earlier work on therapeutic development has focused on eliminating C9orf72 repeat RNAs in order to reduce the production of toxic proteins and slow down neurodegeneration. A common drawback of current approaches, however, is that they struggle to distinguish between the harmful RNA with the repeats and the normal mRNA that encodes an important protein.<\/p>\n

The new findings point to a novel approach that targets either the misdirected splicing or the resulting aberrant RNA. As proof of principle, the researchers designed molecules that selectively bind to the aberrant splice junction, a unique sequence only present in the repeat-containing RNA. Working with their collaborators at Mayo Clinic, the researchers found that these molecules effectively reduced the harmful repeat RNAs and their protein products.<\/p>\n

\u201cFrom the therapeutic perspective, we believe that this is a broadly applicable strategy of identifying unique sequences that could allow us to design therapeutic candidates to selectively target the disease-causing RNA,\u201d Guo explains.<\/p>\n

But there\u2019s another major takeaway of the study.<\/p>\n

\u201cWe must be cautious about categorizing mutations simply according to existing gene models,\u201d says Guo. \u201cBecause it turns out, an intron does not always stay an intron.\u201d<\/p>\n

Other authors of this study include Denethi Wijegunawardana, Tanina Arab, Manasi Agrawal, Jeffrey Zhou, and Jo\u00e3o D. Pereira, from Yale School of Medicine, as well as Udit Sheth, Austin Veire, and Tania Gendron from Mayo Clinic.<\/p>\n

The research reported in this news article was supported by the National Institutes of Health (awards DP2GM132930 and R35GM152208) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was also supported by the McKnight Foundation. Junjie Guo is a New York Stem Cell Foundation\u2212Robertson Neuroscience Investigator. <\/p>\n","protected":false},"excerpt":{"rendered":"Newswise \u2014 It may be time to rethink certain genetic mutations associated with two devastating neurodegenerative disorders\u2014amyotrophic lateral…\n","protected":false},"author":2,"featured_media":63286,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[6810,32704,49,48,40790,316,6808,66],"class_list":{"0":"post-63285","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-all-journal-news","9":"tag-alzheimer","10":"tag-ca","11":"tag-canada","12":"tag-genetic-mutationsneurodegenerative-disordersamyotrophic-lateral-sclerosisalsneurological-diseasedementianeuroscience","13":"tag-genetics","14":"tag-newswise","15":"tag-science"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts\/63285","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/comments?post=63285"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts\/63285\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/media\/63286"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/media?parent=63285"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/categories?post=63285"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/tags?post=63285"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}