PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models
Charcot–Marie–Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated wit...
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2023-03-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/3/832 |
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| author | Kyong-hwa Kang Ji Eun Han Hyunjin Kim Sohee Kim Young Bin Hong Jeanho Yun Soo Hyun Nam Byung-Ok Choi Hyongjong Koh |
| author_facet | Kyong-hwa Kang Ji Eun Han Hyunjin Kim Sohee Kim Young Bin Hong Jeanho Yun Soo Hyun Nam Byung-Ok Choi Hyongjong Koh |
| author_sort | Kyong-hwa Kang |
| collection | DOAJ |
| description | Charcot–Marie–Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated with hereditary neuropathies, including CMT. HSPB8 is a member of the small heat shock protein family sharing a highly conserved α-crystallin domain that is critical to its chaperone activity. In this study, we modeled <i>HSPB8</i> mutant-induced neuropathies in <i>Drosophila</i>. The overexpression of human HSPB8 mutants in <i>Drosophila</i> neurons produced no significant defect in fly development but led to a partial reduction in fly lifespan. Although these <i>HSPB8</i> mutant genes failed to induce sensory abnormalities, they reduced the motor activity of flies and the mitochondrial functions in fly neuronal tissue. The motor defects and mitochondrial dysfunction were successfully restored by <i>PINK1</i> and <i>parkin</i>, which are Parkinson’s disease-associated genes that have critical roles in maintaining mitochondrial function and integrity. Consistently, kinetin riboside, a small molecule amplifying PINK1 activity, also rescued the loss of motor activity in our <i>HSPB8</i> mutant model. |
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| id | doaj.art-91945eac65de41a08c5e7d68bb1b0ed9 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T06:53:43Z |
| publishDate | 2023-03-01 |
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| spelling | doaj.art-91945eac65de41a08c5e7d68bb1b0ed92023-11-17T09:46:18ZengMDPI AGBiomedicines2227-90592023-03-0111383210.3390/biomedicines11030832PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> ModelsKyong-hwa Kang0Ji Eun Han1Hyunjin Kim2Sohee Kim3Young Bin Hong4Jeanho Yun5Soo Hyun Nam6Byung-Ok Choi7Hyongjong Koh8Department of Pharmacology, Dong-A University College of Medicine, Busan 49201, Republic of KoreaDepartment of Pharmacology, Dong-A University College of Medicine, Busan 49201, Republic of KoreaDepartment of Pharmacology, Dong-A University College of Medicine, Busan 49201, Republic of KoreaDepartment of Pharmacology, Dong-A University College of Medicine, Busan 49201, Republic of KoreaNeuroscience Translational Research Solution Center, Dong-A University College of Medicine, Busan 49201, Republic of KoreaNeuroscience Translational Research Solution Center, Dong-A University College of Medicine, Busan 49201, Republic of KoreaPeripheral Neuropathy Research Center, Dong-A University College of Medicine, Busan 49201, Republic of KoreaDepartment of Neurology, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of KoreaDepartment of Pharmacology, Dong-A University College of Medicine, Busan 49201, Republic of KoreaCharcot–Marie–Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated with hereditary neuropathies, including CMT. HSPB8 is a member of the small heat shock protein family sharing a highly conserved α-crystallin domain that is critical to its chaperone activity. In this study, we modeled <i>HSPB8</i> mutant-induced neuropathies in <i>Drosophila</i>. The overexpression of human HSPB8 mutants in <i>Drosophila</i> neurons produced no significant defect in fly development but led to a partial reduction in fly lifespan. Although these <i>HSPB8</i> mutant genes failed to induce sensory abnormalities, they reduced the motor activity of flies and the mitochondrial functions in fly neuronal tissue. The motor defects and mitochondrial dysfunction were successfully restored by <i>PINK1</i> and <i>parkin</i>, which are Parkinson’s disease-associated genes that have critical roles in maintaining mitochondrial function and integrity. Consistently, kinetin riboside, a small molecule amplifying PINK1 activity, also rescued the loss of motor activity in our <i>HSPB8</i> mutant model.https://www.mdpi.com/2227-9059/11/3/832Charcot–Marie–Tooth diseaseperipheral neuropathyHSPB8<i>Drosophila</i>PINK1parkin |
| spellingShingle | Kyong-hwa Kang Ji Eun Han Hyunjin Kim Sohee Kim Young Bin Hong Jeanho Yun Soo Hyun Nam Byung-Ok Choi Hyongjong Koh PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models Biomedicines Charcot–Marie–Tooth disease peripheral neuropathy HSPB8 <i>Drosophila</i> PINK1 parkin |
| title | PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models |
| title_full | PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models |
| title_fullStr | PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models |
| title_full_unstemmed | PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models |
| title_short | PINK1 and Parkin Ameliorate the Loss of Motor Activity and Mitochondrial Dysfunction Induced by Peripheral Neuropathy-Associated HSPB8 Mutants in <i>Drosophila</i> Models |
| title_sort | pink1 and parkin ameliorate the loss of motor activity and mitochondrial dysfunction induced by peripheral neuropathy associated hspb8 mutants in i drosophila i models |
| topic | Charcot–Marie–Tooth disease peripheral neuropathy HSPB8 <i>Drosophila</i> PINK1 parkin |
| url | https://www.mdpi.com/2227-9059/11/3/832 |
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