TY - JOUR
T1 - Peroxisome Metabolism Contributes to PIEZO2-Mediated Mechanical Allodynia
AU - Gong, Yi
AU - Laheji, Fiza
AU - Berenson, Anna
AU - Qian, April
AU - Park, Sang-O.
AU - Kok, Rene
AU - Selig, Martin
AU - Hahn, Ryan
AU - Sadjadi, Reza
AU - Kemp, Stephan
AU - Eichler, Florian
N1 - Funding Information: Funding: This work was supported by grants from NINDS (R01 NS072446, R01 NS082331), the European Leukodystrophy Association (ELA 2019-012I2), the Arrivederci Foundation, the Cure ALD Foundation, the Leblang Charitable Foundation and the Hammer Family Fund for ALD Research and Therapies for Women. Funding Information: Acknowledgments: Imaging was performed in the Microscopy Core of the Program in Membrane Biology, which is partially supported by a Centre for the Study of Inflammatory Bowel Disease Grant DK043351 and a Boston-Area Diabetes and Endocrinology Research Center (BADERC) Award DK057521. The Zeiss confocal system was obtained with grant 1S10OD021577-01. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodys-trophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, Abcd1−/y mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
AB - Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodys-trophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, Abcd1−/y mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
KW - PIEZO2
KW - RNA-seq
KW - X-linked adrenoleukodystrophy (X-ALD)
KW - adrenomyeloneu-ropathy (AMN)
KW - allodynia
KW - dorsal root ganglion (DRG)
KW - glial fibrillary acidic protein (GFAP)
KW - mechanical hypersensitivity
KW - pain
KW - peroxisomes
KW - satellite glial cells (SGCs)
UR - http://www.scopus.com/inward/record.url?scp=85131178539&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells11111842
DO - https://doi.org/10.3390/cells11111842
M3 - Article
C2 - 35681537
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 11
M1 - 1842
ER -