{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:08:33Z","timestamp":1788872913460,"version":"build-2803163510"},"reference-count":111,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by pronounced clinical and molecular heterogeneity, as well as highly interconnected pathogenic pathways. This biological complexity has long hindered efforts to systematically define disease mechanisms and to develop effective, targeted therapies. In recent years, clustered regularly interspaced short palindromic repeats (CRISPR) based functional genomic screening technologies have emerged as powerful tools for large-scale genetic perturbation in cellular, organoid, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models, enabling unbiased interrogation of disease relevant genetic networks and the identification of potential therapeutic targets. In this review, we summarize CRISPR knockout, CRISPR interference, CRISPR activation, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    screening studies in AD, PD, and ALS, with emphasis on pathological phenotypes, experimental models, cell types, validation strategies, and evidence strength. In AD, these screens have identified regulators of amyloid-\u03b2 (A\u03b2) production, Tau homeostasis and propagation, microglial states, neuronal aging, and stress responses. In PD, they have provided insights into \u03b1-synuclein (\u03b1-syn) homeostasis, mitochondrial quality control, lysosomal trafficking, and transplanted dopaminergic neuron survival. In ALS, they have identified modifiers of C9orf72-associated toxicity, repeat-associated non-AUG translation, TAR DNA-binding protein 43 (TDP-43) inclusion formation, and ATXN2 homeostasis. Cross-disease comparison indicates recurring involvement of proteostasis, endolysosomal function, mitochondrial regulation, and cellular stress responses, although individual screening hits show limited overlap and remain strongly influenced by experimental context. Overall, CRISPR-based screening provides a useful framework for identifying candidate disease modifiers, but further validation across complementary human-relevant and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models is required before therapeutic translation.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1831375","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:29:16Z","timestamp":1788870556000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR-based functional genomic screening in neurodegeneration: mechanistic insights into AD, PD, and ALS"],"prefix":"10.3389","volume":"18","author":[{"given":"Feng","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Surgery, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) and Universit\u00e4tsklinikum Erlangen","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Medicine 1, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) and Universit\u00e4tsklinikum Erlangen","place":["Erlangen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anda","family":"He","sequence":"additional","affiliation":[{"name":"Inner Mongolia Autonomous Region Key Laboratory of Medicine and Health: Pharmacology of Mongolian Medicine, Affiliated Hospital of Inner Mongolia Minzu University","place":["Tongliao, Inner Mongolia Autonomous Region, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarentuya","family":"Liang","sequence":"additional","affiliation":[{"name":"The Second Department of Encephalopathy, Affiliated Hospital of Inner Mongolia Minzu University","place":["Tongliao, Inner Mongolia Autonomous Region, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S183","DOI":"10.3233\/JPD-212739","article-title":"Gene therapy for Parkinson's disease associated with GBA1 mutations","volume":"11","author":"Abeliovich","year":"2021","journal-title":"J. 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