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

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(17), С. 9220 - 9220

Опубликована: Авг. 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.

Язык: Английский

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

Heng Wu,

Beisha Tang

и другие.

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Сен. 12, 2024

Язык: Английский

Процитировано

9
Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease DOI Creative Commons

Szilvia Kiraly,

Jack Stanley, Emily R. Eden

и другие.

Antioxidants, Год журнала: 2025, Номер 14(2), С. 125 - 125

Опубликована: Янв. 22, 2025

The perception of lysosomes and mitochondria as entirely separate independent entities that degrade material produce ATP, respectively, has been challenged in recent years not only more complex roles for both organelles, but also an unanticipated level interdependence are being uncovered. Coupled lysosome mitochondrial function dysfunction involve crosstalk between the two organelles which goes beyond quality control lysosome-mediated clearance damaged through mitophagy. Our understanding these essential metabolic transformed by major advances field membrane contact sites biology. We now know play central inter-organelle communication. This importance mitochondria–lysosome contacts (MLCs) cellular homeostasis, evinced growing number diseases have associated with their dysregulation, is starting to be appreciated. How MLCs regulated how coordination other pathways lysosome–mitochondria achieved subjects ongoing scrutiny, this review explores current governing its impact on stress disease.

Язык: Английский

Процитировано

0
The interplay between α-synuclein aggregation and necroptosis in Parkinson’s disease: a spatiotemporal perspective DOI Creative Commons

Huanhuan Xiang

Frontiers in Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Апрель 8, 2025

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the death of dopaminergic neurons and aggregation alpha-synuclein (α-Syn). It presents with prominent motor symptoms, time diagnosis, significant number have already been lost. Current medications can only alleviate symptoms but cannot halt progression. Studies confirmed that both neuronal loss α-Syn are associated necroptosis mechanisms. Necroptosis, regulated form cell death, has recognized as an underexplored hotspot in PD pathogenesis research. In this review, we propose spatiotemporal model progression, highlighting interactions between aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation necroptosis. These processes not drive also contribute to early non-motor offering insights into potential diagnostic markers. Finally, touch upon therapeutic inhibition enhancing current treatments, such L-Dopa. This review aims provide new perspective on identify avenues for development more effective strategies.

Язык: Английский

Процитировано

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

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3929 - 3929

Опубликована: Апрель 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

Язык: Английский

Процитировано

2
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

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(17), С. 9220 - 9220

Опубликована: Авг. 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.

Язык: Английский

Процитировано

0