Pharmacological chaperones restore proteostasis of epilepsy-associated GABAAreceptor variants DOI Creative Commons
Yajuan Wang, Hailey Seibert, Lucie Ahn

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 19, 2023

Abstract Recent advances in genetic diagnosis identified variants genes encoding GABA A receptors as causative for epilepsy. Here, we selected eight disease-associated the α1 subunit of causing mild to severe clinical phenotypes and showed that they are loss function, mainly by reducing folding surface trafficking protein. Furthermore, sought client protein-specific pharmacological chaperones restore function pathogenic receptors. Applications positive allosteric modulators, including Hispidulin TP003, increase functional expression variants. Mechanism action study demonstrated enhance assembly reduce degradation without activating unfolded protein response HEK293T cells human iPSC-derived neurons. Since these compounds cross blood-brain barrier, such a chaperoning strategy holds great promise treat epilepsy receptor-specific manner.

Язык: Английский

HSP47 in human diseases: Navigating pathophysiology, diagnosis and therapy DOI Creative Commons
Essak S. Khan,

Tobias Däinghaus

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(8)

Опубликована: Авг. 1, 2024

Heat shock protein 47 (HSP47) is a chaperone responsible for regulating collagen maturation and transport, directly impacting synthesis levels. Aberrant HSP47 expression or malfunction has been associated with collagen-related disorders, most notably fibrosis. Recent reports have uncovered new functions of in various cellular processes. Hsp47 dysregulation these alternative roles linked to diseases, such as cancer, autoimmune neurodegenerative thereby highlighting its potential both diagnostic biomarker therapeutic target. In this review, we discuss the pathophysiological human tool, clinical screening techniques role target interventions.

Язык: Английский

Процитировано

5
Pharmacological chaperones restore proteostasis of epilepsy-associated GABAA receptor variants DOI Creative Commons
Yajuan Wang, Hailey Seibert, Lucie Ahn

и другие.

Pharmacological Research, Год журнала: 2024, Номер 208, С. 107356 - 107356

Опубликована: Авг. 30, 2024

Recent advances in genetic diagnosis identified variants genes encoding GABA

Язык: Английский

Процитировано

5
GABRA1 frameshift variants impair GABAA receptor proteostasis DOI Creative Commons

Marnie P Williams,

Yajuan Wang, Jing‐Qiong Kang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 29, 2024

Abstract The gamma-aminobutyric acid type A receptor (GABA R) is the most common inhibitory neurotransmitter-gated ion channel in central nervous system. Pathogenic variants genes encoding GABA R subunits can cause dysfunction and lead to genetic epilepsy. Frameshift these result a premature termination codon, producing truncated subunit variants. However, molecular mechanism as well functional implications of frameshift remains inadequately characterized. This study focused on four clinical α 1 (encoded by GABRA1 gene): K401fs (c.1200del), S326fs (c.975del), V290fs (c.869_888del), F272fs (c.813del). These loss one three transmembrane helices, whereas wild α1 has helices. Therefore, serve valuable models evaluate membrane protein biogenesis proteostasis deficiencies. In HEK293T cells, all exhibit significantly reduced trafficking cell surface, resulting essentially non-functional channels. severity deficiency varied among variants, presumably due their specific domain deletions. variant exhibited endoplasmic reticulum (ER) retention activated unfolded response (UPR) varying extents. Our findings revealed that utilize overlapping yet distinct mechanisms impair proteostasis, providing insights into pathogenesis R-associated

Язык: Английский

Процитировано

4
A GluN2B disease-associated variant promotes degradation of NMDA receptors via autophagy DOI Creative Commons

Taylor M. Benske,

Marnie P Williams,

Peipei Zhang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Abstract N-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission and their pathogenic variants can lead to proteostasis defects thus neurological diseases. However, how the network degrades is not well understood. Here, we demonstrated that R519Q GluN2B variant retained in endoplasmic reticulum (ER) fails traffic surface form functional NMDARs. Pharmacological genetic inhibition of autophagy results accumulation this variant, indicating it degraded by autophagy-lysosomal proteolysis pathway. Since has a cytosolic LIR motif, which interact with machinery, disrupting motif impairs autophagic clearance variant. Additionally, recognized ER-phagy receptors, including CCPG1 RTN3L. Our result provides molecular mechanism degradation NMDAR identifies pathway targeted therapeutic intervention disorders dysfunctional Summary NMDA Benske et al. report predispose subunits

Язык: Английский

Процитировано

0
Proteostasis regulation of GABAA receptors in neuronal function and disease DOI
Xi Chen, Yajuan Wang, Ting‐Wei Mu

и другие.

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 186, С. 117992 - 117992

Опубликована: Март 20, 2025

Язык: Английский

Процитировано

0
Pharmacological chaperones restore proteostasis of epilepsy-associated GABAAreceptor variants DOI Creative Commons
Yajuan Wang, Hailey Seibert, Lucie Ahn

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 19, 2023

Abstract Recent advances in genetic diagnosis identified variants genes encoding GABA A receptors as causative for epilepsy. Here, we selected eight disease-associated the α1 subunit of causing mild to severe clinical phenotypes and showed that they are loss function, mainly by reducing folding surface trafficking protein. Furthermore, sought client protein-specific pharmacological chaperones restore function pathogenic receptors. Applications positive allosteric modulators, including Hispidulin TP003, increase functional expression variants. Mechanism action study demonstrated enhance assembly reduce degradation without activating unfolded protein response HEK293T cells human iPSC-derived neurons. Since these compounds cross blood-brain barrier, such a chaperoning strategy holds great promise treat epilepsy receptor-specific manner.

Язык: Английский

Процитировано

3