Pathological Mechanisms and Clinical Aspects of GBA1 Mutation-Associated Parkinson’s Disease

Stoker, Thomas B; Torsney, Kelli M.; Barker, Roger A.

doi:10.15586/codonpublications.parkinsonsdisease.2018.ch3

Cited by 20 publications

(21 citation statements)

References 115 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, mutation of GBA1 gene recently emerged as a common genetic risk associated with PD. Approximately 5% of patients with PD carry a GBA1 mutation, compared to <1% of the control population ( Stoker et al, 2018 ). Moreover, a decrease in Gcase activity has been detected in idiopathic brain tissue of PD ( Chiasserini et al, 2015 ; Parnetti et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment

Jiang

Ming

Yen

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized pathologically by the aggregation of α-synuclein (αS) in the form of Lewy bodies and Lewy neurites. A major challenge in PD therapy is poor efficiency of drug delivery to the brain due to the blood–brain barrier (BBB). For this reason, nanomaterials, with significant advantages in drug delivery, have gained attention. On the other hand, recent studies have shown that nanoparticles can promote αS aggregation in salt solution. Therefore, we tested if nanoparticles could have the same effect in cell models. We found that nanoparticle can induce cells to form αS inclusions as shown in immunocytochemistry, and detergent-resistant αS aggregates as shown in biochemical analysis; and nanoparticles of smaller size can induce more αS inclusions. Moreover, the induction of αS inclusions is in part dependent on endolysosomal impairment and the affinity of αS to nanoparticles. More importantly, we found that the abnormally high level of endogenous lysosomotropic biomolecules (e.g., sphingosine), due to impairing the integrity of endolysosomes could be a determinant factor for the susceptibility of cells to nanoparticle-induced αS aggregation; and deletion of GBA1 gene to increase the level of intracellular sphingosine can render cultured cells more susceptible to the formation of αS inclusions in response to nanoparticle treatment. Ultrastructural examination of nanoparticle-treated cells revealed that the induced inclusions contained αS-immunopositive membranous structures, which were also observed in inclusions seeded by αS fibrils. These results suggest caution in the use of nanoparticles in PD therapy. Moreover, this study further supports the role of endolysosomal impairment in PD pathogenesis and suggests a possible mechanism underlying the formation of membrane-associated αS pathology.

show abstract

Section: Resultsmentioning

confidence: 99%

Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment

Jiang

Ming

Yen

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…As lysosomes are the end points for the degradation of damaged mitochondria via mitophagy, PD associated mutations that affect the function of lysosomes also impair mitophagy, further contributing to the PD pathogenesis. Heterozygous mutations in glucosylceramidase beta (GBA), a lysosomal enzyme that converts glucosylceramide to ceramide and glucose, is one of the most common genetic risk factors for PD pathogenesis, contributing to 7–20% of all PD cases ( Stoker et al, 2018 ). Interestingly, homozygous mutations in GBA cause Gaucher disease (GD), the most common lysosomal storage disorder.…”

Section: Unravelling the Molecular Mechanisms Of Mitophagy Dysregulat...mentioning

confidence: 99%

Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns

Jetto

Nambiar

Manjithaya

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Macroautophagy (henceforth autophagy) an evolutionary conserved intracellular pathway, involves lysosomal degradation of damaged and superfluous cytosolic contents to maintain cellular homeostasis. While autophagy was initially perceived as a bulk degradation process, a surfeit of studies in the last 2 decades has revealed that it can also be selective in choosing intracellular constituents for degradation. In addition to the core autophagy machinery, these selective autophagy pathways comprise of distinct molecular players that are involved in the capture of specific cargoes. The diverse organelles that are degraded by selective autophagy pathways are endoplasmic reticulum (ERphagy), lysosomes (lysophagy), mitochondria (mitophagy), Golgi apparatus (Golgiphagy), peroxisomes (pexophagy) and nucleus (nucleophagy). Among these, the main focus of this review is on the selective autophagic pathway involved in mitochondrial turnover called mitophagy. The mitophagy pathway encompasses diverse mechanisms involving a complex interplay of a multitude of proteins that confers the selective recognition of damaged mitochondria and their targeting to degradation via autophagy. Mitophagy is triggered by cues that signal the mitochondrial damage such as disturbances in mitochondrial fission-fusion dynamics, mitochondrial membrane depolarisation, enhanced ROS production, mtDNA damage as well as developmental cues such as erythrocyte maturation, removal of paternal mitochondria, cardiomyocyte maturation and somatic cell reprogramming. As research on the mechanistic aspects of this complex pathway is progressing, emerging roles of new players such as the NIPSNAP proteins, Miro proteins and ER-Mitochondria contact sites (ERMES) are being explored. Although diverse aspects of this pathway are being investigated in depth, several outstanding questions such as distinct molecular players of basal mitophagy, selective dominance of a particular mitophagy adapter protein over the other in a given physiological condition, molecular mechanism of how specific disease mutations affect this pathway remain to be addressed. In this review, we aim to give an overview with special emphasis on molecular and signalling pathways of mitophagy and its dysregulation in neurodegenerative disorders.

show abstract

“…While it is estimated that between 7% and 12% of patients with PD carry a mutation in the GBA1 gene, only a minority of GBA1 mutation carriers actually develop PD symptoms [ 20 ]. Given the lysosomal-related function of GBA1, mutations provoke general autophagy defects that would also be predicted to disrupt mitophagy [ 85 ]. Additionally, mice with the GBA1 knock-in mutation L444P have been reported to have impaired mitochondrial function and mitophagy [ 86 ] ( Figure 1 — mitochondrial degradation).…”

Section: Mitophagy Defects In Pdmentioning

confidence: 99%

Parkinson's disease and mitophagy: an emerging role for LRRK2

Singh

Ganley

2021

Biochemical Society Transactions

View full text Add to dashboard Cite

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

show abstract

Pathological Mechanisms and Clinical Aspects of GBA1 Mutation-Associated Parkinson’s Disease

Cited by 20 publications

References 115 publications

Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment

Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment

Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns

Parkinson's disease and mitophagy: an emerging role for LRRK2

Contact Info

Product

Resources

About