{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:37:36Z","timestamp":1790613456383,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Start-up fund\u2014Vickie &amp; Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>Background and Objectives: Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2\/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C&gt;T was discovered in an adult patient with severe sensory\u2013motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase activity to result in a correctly folded protein(s). In this study, we aimed to investigate the effects of the heterozygous DNAJB2 c.823+6C&gt;T mutation on the stress response of DNAJB2 in fibroblasts obtained from the neuropathy patient. Methods: The fibroblasts were subjected to one hour of heat shock at 42 \u00b0C, and the time course of expression levels of DNAJB2 was established. Additionally, we evaluated the therapeutic efficacy of Cystamine, which has been shown to modulate DNAJB2 levels in cellular and animal models of Huntington\u2019s disease. Results: Our results revealed reduced baseline levels of DNAJB2 between the mutant and control fibroblasts. Importantly the mutant cells exhibited a diminished response to heat shock. Thus, the mutation affects the upregulation of DNAJB2 under stress, possibly contributing to the pathogenesis of sensory\u2013motor polyneuropathy. A 48-h pretreatment with 150 \u03bcM of Cystamine increased the levels of DNAJB2 in both the control and patient\u2019s fibroblasts. Conclusions: To the best of our knowledge, this is the first study to explore this mutant form of DNAJB2 in neuropathy. The study demonstrated that the heterozygous DNAJB2 c.823+6C&gt;T mutation leads to impaired DNAJB2 response to heat shock in the fibroblasts. Cystamine showed promise in restoring DNAJB2 expression, highlighting the need for further research into targeted therapeutic strategies for DNAJB2-related disorders.<\/jats:p>","DOI":"10.3390\/neurolint17050073","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T06:18:51Z","timestamp":1746771531000},"page":"73","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with DNAJB2\/HSJ1 Mutation: Cystamine as a Potential Therapeutic Intervention"],"prefix":"10.3390","volume":"17","author":[{"given":"Raj Kumar","family":"Pradhan","sequence":"first","affiliation":[{"name":"Jefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1192-8149","authenticated-orcid":false,"given":"Nikolas G.","family":"Kinney","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid K.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8318-7533","authenticated-orcid":false,"given":"Hristelina","family":"Ilieva","sequence":"additional","affiliation":[{"name":"Jefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/ana.22684","article-title":"A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation","volume":"71","author":"Blumen","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1212\/WNL.0000000000000966","article-title":"HSJ1-related hereditary neuropathies: Novel mutations and extended clinical spectrum","volume":"83","author":"Gess","year":"2014","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jmoldx.2015.10.005","article-title":"Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy","volume":"18","author":"Lupo","year":"2016","journal-title":"J. Mol. Diagn."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1136\/jnnp-2015-312890","article-title":"Phenotype and natural history of inherited neuropathies caused by HSJ1 c.352+1G & A mutation","volume":"87","author":"Frasquet","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/humu.23055","article-title":"Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism","volume":"37","author":"Sanchez","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e154","DOI":"10.1016\/j.parkreldis.2015.10.361","article-title":"Distal hereditary motor neuropathy with HSJ1 chaperone mutation, presenting with peripheral motor neuropathy, associated to parkinsonism, and cerebellar ataxia. Case report","volume":"22","author":"Teive","year":"2016","journal-title":"Park. Relat. Disorders"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1042\/bj2840469","article-title":"Human homologues of the bacterial heat-shock protein DnaJ are preferentially expressed in neurons","volume":"284","author":"Cheetham","year":"1992","journal-title":"Biochem. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19087","DOI":"10.1074\/jbc.M212349200","article-title":"The Chaperone Environment at the Cytoplasmic Face of the Endoplasmic Reticulum Can Modulate Rhodopsin Processing and Inclusion Formation","volume":"278","author":"Chapple","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrm2941","article-title":"The HSP70 chaperone machinery: J proteins as drivers of functional specificity","volume":"11","author":"Kampinga","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.cub.2005.04.058","article-title":"HSJ1 Is a Neuronal Shuttling Factor for the Sorting of Chaperone Clients to the Proteasome","volume":"15","author":"Westhoff","year":"2005","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1172\/JCI27607","article-title":"Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase","volume":"116","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.2353\/ajpath.2010.090663","article-title":"DNAJB2 Expression in Normal and Diseased Human and Mouse Skeletal Muscle","volume":"176","author":"Claeys","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R1901","DOI":"10.1152\/ajpregu.00847.2007","article-title":"Gene expression profiling in human skeletal muscle during recovery from eccentric exercise","volume":"294","author":"Mahoney","year":"2008","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_14","first-page":"99","article-title":"Regulation of 70-kDa heat-shock-protein ATPase activity and substrate binding by human DnaJ-like proteins, HSJ1a and HSJ1b","volume":"226","author":"Cheetham","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/sj.mt.6300163","article-title":"Hsp40 Molecules That Target to the Ubiquitin-proteasome System Decrease Inclusion Formation in Models of Polyglutamine Disease","volume":"15","author":"Howarth","year":"2007","journal-title":"Mol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3233\/JHD-180312","article-title":"Cysteamine Protects Neurons from Mutant Huntingtin Toxicity1","volume":"8","author":"Arbez","year":"2019","journal-title":"J. Huntington\u2019s Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.neurobiolaging.2005.04.001","article-title":"The protective effects of cystamine in the R6\/2 Huntington\u2019s disease mouse involve mechanisms other than the inhibition of tissue transglutaminase","volume":"27","author":"Bailey","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3825","DOI":"10.1074\/jbc.M205812200","article-title":"Cystamine Inhibits Caspase Activity","volume":"278","author":"Lesort","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Paul, B.D., and Snyder, S.H. (2019). Therapeutic Applications of Cysteamine and Cystamine in Neurodegenerative and Neuropsychiatric Diseases. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.01315"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4250","DOI":"10.1093\/nar\/gkm402","article-title":"Aberrant 5\u2032 splice sites in human disease genes: Mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization","volume":"35","author":"Buratti","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/hmg\/7.5.919","article-title":"Statistical features of human exons and their flanking regions","volume":"7","author":"Zhang","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zarouchlioti, C., Parfitt, D.A., Li, W., Gittings, L.M., and Cheetham, M.E. (2018). DNAJ Proteins in neurodegeneration: Essential and protective factors. Philos. Trans. R. Soc. B Biol. Sci., 373.","DOI":"10.1098\/rstb.2016.0534"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.celrep.2015.07.023","article-title":"Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy","volume":"12","author":"Harel","year":"2015","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1093\/hmg\/ddad058","article-title":"Extension of the DNAJB2a isoform in a dominant neuromyopathy family","volume":"32","author":"Sarparanta","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1111\/ene.15326","article-title":"DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening","volume":"29","author":"Saveri","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1002\/bies.20843","article-title":"The role of the ubiquitin proteasome system in synapse remodeling and neurodegenerative diseases","volume":"30","author":"Ding","year":"2008","journal-title":"BioEssays"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1379\/1466-1268(2000)005<0003:EOCGBH>2.0.CO;2","article-title":"Expression of cholesteryl glucoside by heat shock in human fibroblasts","volume":"5","author":"Kunimoto","year":"2000","journal-title":"Cell Stress Chaperones"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1042\/bj3080743","article-title":"Heat shock of human synovial and dermal fibroblasts induces delayed up-regulation of collagenase-gene expression","volume":"308","author":"Hitraya","year":"1995","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.3390\/ijms10114963","article-title":"Heat shock-induced three-dimensional-like proliferation of normal human fibroblasts mediated by pressed silk","volume":"10","author":"Hiragami","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13024-017-0208-6","article-title":"The heat shock response in neurons and astroglia and its role in neurodegenerative diseases","volume":"12","author":"Ooi","year":"2017","journal-title":"Mol. Neurodegener."}],"container-title":["Neurology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8377\/17\/5\/73\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:29:57Z","timestamp":1760030997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8377\/17\/5\/73"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":30,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["neurolint17050073"],"URL":"https:\/\/doi.org\/10.3390\/neurolint17050073","relation":{},"ISSN":["2035-8377"],"issn-type":[{"value":"2035-8377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,9]]}}}