Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention
<b>Background and Objectives:</b> 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...
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2025-05-01
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| author | Raj Kumar Pradhan Nikolas G. Kinney Brigid K. Jensen Hristelina Ilieva |
| author_facet | Raj Kumar Pradhan Nikolas G. Kinney Brigid K. Jensen Hristelina Ilieva |
| author_sort | Raj Kumar Pradhan |
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| description | <b>Background and Objectives:</b> 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>T was discovered in an adult patient with severe sensory–motor 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>T mutation on the stress response of DNAJB2 in fibroblasts obtained from the neuropathy patient. <b>Methods:</b> The fibroblasts were subjected to one hour of heat shock at 42 °C, 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’s disease. <b>Results:</b> 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–motor polyneuropathy. A 48-h pretreatment with 150 μM of Cystamine increased the levels of DNAJB2 in both the control and patient’s fibroblasts. <b>Conclusions:</b> 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>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. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-5ebc3cd6544b4275a2ea5a56283f4a782025-08-20T03:47:58ZengMDPI AGNeurology International2035-83772025-05-011757310.3390/neurolint17050073Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic InterventionRaj Kumar Pradhan0Nikolas G. Kinney1Brigid K. Jensen2Hristelina Ilieva3Jefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USAJefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USAJefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USAJefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USA<b>Background and Objectives:</b> 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>T was discovered in an adult patient with severe sensory–motor 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>T mutation on the stress response of DNAJB2 in fibroblasts obtained from the neuropathy patient. <b>Methods:</b> The fibroblasts were subjected to one hour of heat shock at 42 °C, 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’s disease. <b>Results:</b> 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–motor polyneuropathy. A 48-h pretreatment with 150 μM of Cystamine increased the levels of DNAJB2 in both the control and patient’s fibroblasts. <b>Conclusions:</b> 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>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.https://www.mdpi.com/2035-8377/17/5/73neuropathyheat shock proteinsDNAJB2HSP40HSJ1Cystamine |
| spellingShingle | Raj Kumar Pradhan Nikolas G. Kinney Brigid K. Jensen Hristelina Ilieva Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention Neurology International neuropathy heat shock proteins DNAJB2 HSP40 HSJ1 Cystamine |
| title | Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention |
| title_full | Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention |
| title_fullStr | Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention |
| title_full_unstemmed | Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention |
| title_short | Impaired DNAJB2 Response to Heat Shock in Fibroblasts from a Neuropathy Patient with <i>DNAJB2/HSJ1</i> Mutation: Cystamine as a Potential Therapeutic Intervention |
| title_sort | impaired dnajb2 response to heat shock in fibroblasts from a neuropathy patient with i dnajb2 hsj1 i mutation cystamine as a potential therapeutic intervention |
| topic | neuropathy heat shock proteins DNAJB2 HSP40 HSJ1 Cystamine |
| url | https://www.mdpi.com/2035-8377/17/5/73 |
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