The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts DOI Open Access

Laura Patricia Perez-Abshana,

Miguel Mendivil‐Perez, Marlene Jiménez-Del-Río

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9220 - 9220

Published: Aug. 25, 2024

Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as result of the loss dopaminergic (DAergic) neurons pars compacta in substantia nigra protein aggregates alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental genetic factors have suggested major contributors to disease. Mutations glucosidase beta acid 1 (GBA1) gene, which encodes lysosomal glucosylceramidase (GCase) enzyme, are one risks for PD. We found that GBA1 K198E fibroblasts but WT showed reduced catalytic activity heterozygous mutant GCase by −70% expression levels increased 3.68-fold; acidification autophagy vacuoles (e.g., autophagosomes, lysosomes, autolysosomes) +1600%; augmented autophagosome Beclin-1 (+133%) LC3-II (+750%), lysosomal–autophagosome fusion LAMP-2 (+107%); accumulation lysosomes (+400%); decreased mitochondrial membrane potential (∆Ψm) −19% Parkin remained unperturbed; oxidized DJ-1Cys106-SOH +900%, evidence oxidative stress; phosphorylated LRRK2 at Ser935 (+1050%) along with α-synuclein (α-Syn) pathological residue Ser129 (+1200%); executer apoptotic caspase 3 (cleaved 3) +733%. exposure neutoxin rotenone (ROT, μM) exacerbated autophagy–lysosomal system, stress, apoptosis markers, ROT moderately those markers fibroblasts. concluded mutation endogenously primes skin toward dysfunction, OS, apoptosis. Our findings suggest biochemically molecularly equivalent response exposed ROT.

Language: Английский

Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease DOI Creative Commons
Xuxiang Zhang,

Heng Wu,

Beisha Tang

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 12, 2024

Language: Английский

Citations

9
Mild cognitive impairment in Parkinson's disease: current view DOI Creative Commons
K. A. Jellinger

Frontiers in Cognition, Journal Year: 2024, Volume and Issue: 3

Published: April 5, 2024

Parkinson's disease (PD), the most common motor movement disorder and second neurodegenerative after Alzheimer's (AD), is often preceded by a period of mild cognitive impairment (MCI), which associated with variety domains including executive function, attention, visuospatial abilities memory. MCI, risk factor for developing dementia, affects around 30% de novo PD patients can increase to 75% more than 10 years. While 30–40% remain in MCI state, up 60% will convert dementia. Characteristic findings are slowing EEG rhythms, frontotemporal hypoperfusion, decreased functional connectivity default mode attentional networks, prefrontal basal-ganglia-cortical circuits, manifests prior clinical symptoms overt brain atrophy. The heterogeneity phenotypes suggests that process multiple neuronal networks neuromodulatory systems may be superimposed Lewy body Alzheimer's-related or other co-pathologies. Sparse neuropathological data PD-MCI revealed heterogenous picture various morphological changes similar diseases. This review highlights essential epidemiological, clinical, neuroimaging PD-MCI, available biomarkers, discusses pathobiological mechanisms involved its development. In view complex pathogenesis, well-designed longitudinal clinico-pathological studies warranted clarify alterations leading PD, supported fluid biomarkers as basis early diagnosis future adequate treatment modalities this debilitating disorder.

Language: Английский

Citations

7
Effects and mechanisms of water extract of Uraria crinit a on manganese chloride-induced apoptosis in SH-SY5Y cells DOI Creative Commons
Jin–Tung Liang,

Weiwei Yin,

Duanzhuo Li

et al.

CyTA - Journal of Food, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 11, 2025

Language: Английский

Citations

0
Gene therapies for neurogenetic disorders DOI Creative Commons
Orrin Devinsky, Jeff Coller, Rebecca C. Ahrens‐Nicklas

et al.

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations DOI Open Access
Paola Lenzi, Gloria Lazzeri, Michela Ferrucci

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3929 - 3929

Published: April 1, 2024

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on pathophysiology Parkinson’s disease (PD). line with this, alpha-syn considered to be guilty protein in process, it may targeted through precision medicine modify progression. Therefore, designing specific tools block aggregation spreading represents effort development disease-modifying therapies PD. The present article analyzes concrete evidence about significance within LBs. this effort, some dogmas are challenged. concerns question whether more abundant compared other proteins Again, occurrence non-protein constituents scrutinized. Finally, LBs causing PD questioned. These revisited concepts helpful process validating which proteins, organelles, pathways likely involved damage meso-striatal dopamine neurons brain regions

Language: Английский

Citations

2
Lipids and α-Synuclein: adding further variables to the equation DOI Creative Commons
Jana Schepers, Timo Löser, Christian Behl

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Aug. 12, 2024

Graphical Abstract The graphical abstract summarises factors that might lead to lipid changes and possible influences of on synucleinopathies.

Language: Английский

Citations

0
The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts DOI Open Access

Laura Patricia Perez-Abshana,

Miguel Mendivil‐Perez, Marlene Jiménez-Del-Río

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9220 - 9220

Published: Aug. 25, 2024

Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as result of the loss dopaminergic (DAergic) neurons pars compacta in substantia nigra protein aggregates alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental genetic factors have suggested major contributors to disease. Mutations glucosidase beta acid 1 (GBA1) gene, which encodes lysosomal glucosylceramidase (GCase) enzyme, are one risks for PD. We found that GBA1 K198E fibroblasts but WT showed reduced catalytic activity heterozygous mutant GCase by −70% expression levels increased 3.68-fold; acidification autophagy vacuoles (e.g., autophagosomes, lysosomes, autolysosomes) +1600%; augmented autophagosome Beclin-1 (+133%) LC3-II (+750%), lysosomal–autophagosome fusion LAMP-2 (+107%); accumulation lysosomes (+400%); decreased mitochondrial membrane potential (∆Ψm) −19% Parkin remained unperturbed; oxidized DJ-1Cys106-SOH +900%, evidence oxidative stress; phosphorylated LRRK2 at Ser935 (+1050%) along with α-synuclein (α-Syn) pathological residue Ser129 (+1200%); executer apoptotic caspase 3 (cleaved 3) +733%. exposure neutoxin rotenone (ROT, μM) exacerbated autophagy–lysosomal system, stress, apoptosis markers, ROT moderately those markers fibroblasts. concluded mutation endogenously primes skin toward dysfunction, OS, apoptosis. Our findings suggest biochemically molecularly equivalent response exposed ROT.

Language: Английский

Citations

0