{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:56:24Z","timestamp":1777895784055,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T00:00:00Z","timestamp":1661040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Associazione Italiana per la Ricerca sul Cancro","award":["IG 23116"],"award-info":[{"award-number":["IG 23116"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Globoid cell leukodystrophy (GLD), or Krabbe disease, is a neurodegenerative sphingolipidosis caused by genetic deficiency of lysosomal \u03b2-galactosylceramidase (GALC), characterized by neuroinflammation and demyelination of the central (CNS) and peripheral nervous system. The acute phase protein long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and a regulator of innate immunity. Growing evidence points to the involvement of PTX3 in neurodegeneration. However, the expression and role of PTX3 in the neurodegenerative\/neuroinflammatory processes that characterize GLD remain unexplored. Here, immunohistochemical analysis of brain samples from Krabbe patients showed that macrophages and globoid cells are intensely immunoreactive for PTX3. Accordingly, Ptx3 expression increases throughout the course of the disease in the cerebrum, cerebellum, and spinal cord of GALC-deficient twitcher (Galctwi\/twi) mice, an authentic animal model of GLD. This was paralleled by the upregulation of proinflammatory genes and M1-polarized macrophage\/microglia markers and of the levels of PTX3 protein in CNS and plasma of twitcher animals. Crossing of Galctwi\/twi mice with transgenic PTX3 overexpressing animals (hPTX3 mice) demonstrated that constitutive PTX3 overexpression reduced the severity of clinical signs and the upregulation of proinflammatory genes in the spinal cord of P35 hPTX3\/Galctwi\/twi mice when compared to Galctwi\/twi littermates, leading to a limited increase of their life span. However, this occurred in the absence of a significant impact on the histopathological findings and on the accumulation of the neurotoxic metabolite psychosine when evaluated at this late time point of the disease. In conclusion, our results provide the first evidence that PTX3 is produced in the CNS of GALC-deficient Krabbe patients and twitcher mice. PTX3 may exert a protective role by reducing the neuroinflammatory response that occurs in the spinal cord of GALC-deficient animals.<\/jats:p>","DOI":"10.3390\/ijms23169436","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T22:23:13Z","timestamp":1661120593000},"page":"9436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["\u03b2-Galactosylceramidase Deficiency Causes Upregulation of Long Pentraxin-3 in the Central Nervous System of Krabbe Patients and Twitcher Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Daniela","family":"Coltrini","sequence":"first","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adwaid Manu Krishna","family":"Chandran","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirella","family":"Belleri","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5662-8978","authenticated-orcid":false,"given":"Pietro L.","family":"Poliani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Cominelli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1671-5671","authenticated-orcid":false,"given":"Francesca","family":"Pagani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4941-6739","authenticated-orcid":false,"given":"Miriam","family":"Capra","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4996-7995","authenticated-orcid":false,"given":"Stefano","family":"Calza","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Prioni","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4194-4804","authenticated-orcid":false,"given":"Laura","family":"Mauri","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0252-2593","authenticated-orcid":false,"given":"Alessandro","family":"Prinetti","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia K.","family":"Kofler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224-1334, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-6777","authenticated-orcid":false,"given":"Maria L.","family":"Escolar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224-1334, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4398-8376","authenticated-orcid":false,"given":"Marco","family":"Presta","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1073\/pnas.66.2.302","article-title":"Globoid cell leucodystrophy (Krabbe\u2019s disease): Deficiency of galactocerebroside beta-galactosidase","volume":"66","author":"Suzuki","year":"1970","journal-title":"Proc. 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