Mitochondria–lysosome crosstalk in GBA1-associated Parkinson’s disease

Sahyadri, M; Nadiga, Abhishek P. R.; Mehdi, Seema; Mruthunjaya, K.; Nayak, Pawan G.; Parihar, Vipan K.; Manjula, S. N.

doi:10.1007/s13205-022-03261-9

3 Biotech

2022

DOI: 10.1007/s13205-022-03261-9

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Mitochondria–lysosome crosstalk in GBA1-associated Parkinson’s disease

M Sahyadri

Abhishek P. R. Nadiga

Seema Mehdi

et al.

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Cited by 3 publications

(1 citation statement)

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“…In addition, upon antimycin-A treatment, mitochondria showed an altered morphology (shrank/less elongated, see Figure S12). Mitochondrial dysfunction can be attributable to either high local ROS concentration or lysosome damage leading to the so-called mitochondria–lysosome crosstalk, known to be involved in aging and neurodegenerative diseases. − The confocal microscopy analysis reported in Figures and S12 shows that Pt-nanozyme internalization, in addition to lysosomes, can also preserve mitochondria from ROS and, by protecting the lysosomal–mithochondria axes, can prevent cell apoptosis.…”

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confidence: 99%

Catalytic Bioswitch of Platinum Nanozymes: Mechanistic Insights of Reactive Oxygen Species Scavenging in the Neurovascular Unit

et al. 2023

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Oxidative stress is known to be the cause of several neurovascular diseases, including neurodegenerative disorders, since the increase of reactive oxygen species (ROS) levels can lead to cellular damage, blood–brain barrier leaking, and inflammatory pathways. Herein, we demonstrate the therapeutic potential of 5 nm platinum nanoparticles (PtNPs) to effectively scavenge ROS in different cellular models of the neurovascular unit. We investigated the mechanism underlying the PtNP biological activities, analyzing the influence of the evolving biological environment during particle trafficking and disclosing a key role of the protein corona, which elicited an effective switch-off of the PtNP catalytic properties, promoting their selective in situ activity. Upon cellular internalization, the lysosomal environment switches on and boosts the enzyme-like activity of the PtNPs, acting as an intracellular “catalytic microreactor” exerting strong antioxidant functionalities. Significant ROS scavenging was observed in the neurovascular cellular models, with an interesting protective mechanism of the Pt-nanozymes along lysosomal–mitochondrial axes.

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confidence: 99%

Catalytic Bioswitch of Platinum Nanozymes: Mechanistic Insights of Reactive Oxygen Species Scavenging in the Neurovascular Unit

et al. 2023

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Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

Calderón‐Garcidueñas

Torres‐Jardón²,

Greenough³

et al. 2023

Front. Neurol.

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Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ1 − 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

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GBA1-Associated Parkinson’s Disease Is a Distinct Entity

Skrahin,

Horowitz,

Istaiti

et al. 2024

IJMS

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GBA1-associated Parkinson’s disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson’s disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: ‘haploinsufficiency,’ where a single functional gene copy fails to produce a sufficient amount of GCase, and ‘gain of function,’ where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the ‘gain of function’ mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.

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Mitochondria–lysosome crosstalk in GBA1-associated Parkinson’s disease

Cited by 3 publications

References 103 publications

Catalytic Bioswitch of Platinum Nanozymes: Mechanistic Insights of Reactive Oxygen Species Scavenging in the Neurovascular Unit

Catalytic Bioswitch of Platinum Nanozymes: Mechanistic Insights of Reactive Oxygen Species Scavenging in the Neurovascular Unit

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

GBA1-Associated Parkinson’s Disease Is a Distinct Entity

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