TY - JOUR
T1 - Abnormal activation of MAPKs pathways and inhibition of autophagy in a group of patients with Zellweger spectrum disorders and X-linked adrenoleukodystrophy
AU - Gragnaniello, Vincenza
AU - Gueraldi, Daniela
AU - Puma, Andrea
AU - Commone, Anna
AU - Cazzorla, Chiara
AU - Loro, Christian
AU - Porcù, Elena
AU - Stornaiuolo, Maria
AU - Miglioranza, Paolo
AU - Salviati, Leonardo
AU - Wanders, Ronald J. A.
AU - Burlina, Alberto
N1 - Funding Information: Open access funding provided by Università degli Studi di Padova. Part of the work was funded by Cometa A.S.M.M.E.–Associazione Studio Malattie Metaboliche Ereditarie—ONLUS, Padova Italy. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background: Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs. Methods: Three patients with ZSD (2 M, 1 F; age range 8–17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy. Results: X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20–19.92) and 2.90-fold (range 1.43–4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio. Conclusions: In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.
AB - Background: Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs. Methods: Three patients with ZSD (2 M, 1 F; age range 8–17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy. Results: X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20–19.92) and 2.90-fold (range 1.43–4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio. Conclusions: In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.
KW - Antioxidants
KW - Autophagy
KW - JNK
KW - LC3
KW - Mitogen-activated protein kinases (MAPKs)
KW - Oxidative stress
KW - Peroxisomal disorders
KW - X-linked adrenoleukodystrophy
KW - Zellweger spectrum disorders
KW - p38
UR - http://www.scopus.com/inward/record.url?scp=85176958551&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13023-023-02940-x
DO - https://doi.org/10.1186/s13023-023-02940-x
M3 - Article
C2 - 37974207
SN - 1750-1172
VL - 18
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 358
ER -