The function of lysosomes and their role in Parkinson’s disease

Neuroforum ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 43-51
Author(s):  
Friederike Zunke
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lysosomal Storage ◽  
Lysosomal Function ◽  
Potential Risk Factors ◽  
Lysosomal Membrane Proteins ◽  
Novel Therapeutic Strategies ◽  
Turn Over ◽  
Soluble Enzymes ◽  
Cellular Organelles

AbstractLysosomes are cellular organelles that are important for the degradation and recycling of various biomolecules. Specialized lysosomal membrane proteins, as well as soluble enzymes, are important for the efficient turn-over of lysosomal substrates. A deficiency in the degradative capacity of lysosomes leads to severe pathologies referred to as lysosomal storage disorders. There is increasing evidence for the importance of lysosomal function in neurodegenerative disorders, including Parkinson’s disease. One reason for this might be the vulnerability of neuronal cells. Since neurons do not undergo further cell division, non-degraded substrates accumulate in aging cells, causing a buildup of toxicity. Recent genomic screenings identified a number of lysosome-associated genes as potential risk factors for Parkinson’s disease, which are discussed in this review. Moreover, it is outlined how targeting lysosomal function might help in developing novel therapeutic strategies.

scholarly journals The Emerging Role of the Lysosome in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2399
Author(s):  
Alba Navarro-Romero ◽  
Marta Montpeyó ◽  
Marta Martinez-Vicente
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Lysosomal Storage Diseases ◽  
Genetic Risk Factors ◽  
Brain Regions ◽  
Lysosomal Storage ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson’s disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson’s disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

scholarly journals Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

2021 ◽  
Author(s):  
Daniel Erskine ◽  
David Koss ◽  
Viktor I. Korolchuk ◽  
Tiago F. Outeiro ◽  
Johannes Attems ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Mitochondrial Diseases ◽  
Model Systems ◽  
Lipid Homeostasis ◽  
Lysosomal Storage ◽  
Iron Storage ◽  
Monogenic Disorders ◽  
Storage Disorders

AbstractAccumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

scholarly journals Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 105 ◽  
Author(s):  
Maria Zella ◽  
Judith Metzdorf ◽  
Friederike Ostendorf ◽  
Fabian Maass ◽  
Siegfried Muhlack ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glial Cell ◽  
Dopaminergic Neurons ◽  
Basic Research ◽  
Alpha Synuclein ◽  
Models Of Disease ◽  
Novel Therapeutic Strategies ◽  
Lymphocyte Populations

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

scholarly journals The Association Between Lysosomal Storage Disorder Genes and Parkinson’s Disease: A Large Cohort Study in Chinese Mainland Population

2021 ◽  
Vol 13 ◽  
Author(s):  
Yu-wen Zhao ◽  
Hong-xu Pan ◽  
Zhenhua Liu ◽  
Yige Wang ◽  
Qian Zeng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Lysosomal Storage Disorder ◽  
Rare Variants ◽  
Late Onset ◽  
Chinese Mainland ◽  
Lysosomal Storage ◽  
Post Translational Modification ◽  
Storage Disorder

Background: Recent years have witnessed an increasing number of studies indicating an essential role of the lysosomal dysfunction in Parkinson’s disease (PD) at the genetic, biochemical, and cellular pathway levels. In this study, we investigated the association between rare variants in lysosomal storage disorder (LSD) genes and Chinese mainland PD.Methods: We explored the association between rare variants of 69 LSD genes and PD in 3,879 patients and 2,931 controls from Parkinson’s Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) using next-generation sequencing, which were analyzed by using the optimized sequence kernel association test.Results: We identified the significant burden of rare putative LSD gene variants in Chinese mainland patients with PD. This association was robust in familial or sporadic early-onset patients after excluding the GBA variants but not in sporadic late-onset patients. The burden analysis of variant sets in genes of LSD subgroups revealed a suggestive significant association between variant sets in genes of sphingolipidosis deficiency disorders and familial or sporadic early-onset patients. In contrast, variant sets in genes of sphingolipidoses, mucopolysaccharidoses, and post-translational modification defect disorders were suggestively associated with sporadic late-onset patients. Then, SMPD1 and other four novel genes (i.e., GUSB, CLN6, PPT1, and SCARB2) were suggestively associated with sporadic early-onset or familial patients, whereas GALNS and NAGA were suggestively associated with late-onset patients.Conclusion: Our findings supported the association between LSD genes and PD and revealed several novel risk genes in Chinese mainland patients with PD, which confirmed the importance of lysosomal mechanisms in PD pathogenesis. Moreover, we identified the genetic heterogeneity in early-onset and late-onset of patients with PD, which may provide valuable suggestions for the treatment.

scholarly journals Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis

2020 ◽  
Vol 40 (19) ◽  
Author(s):  
Yasir H. Qureshi ◽  
Penelope Baez ◽  
Christiane Reitz
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Endosomal Trafficking ◽  
Lysosomal Storage ◽  
Ceroid Lipofuscinosis ◽  
Common Neurodegenerative Disorder

ABSTRACT Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson’s disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer’s disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL’s causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer and others causing endolysosomal dysfunction. AD has over 25 causative genes/risk factors, with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL with retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD, and discuss how NCL, AD, and PD converge on a shared molecular pathway. We also discuss this pathway’s role in microglia and neurons, cell populations which are critical to proper brain homeostasis and whose dysfunction plays a key role in neurodegeneration.

scholarly journals Chaperone-Mediated Autophagy and Mitochondrial Homeostasis in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-7
Author(s):  
Ruixin Yang ◽  
Guodong Gao ◽  
Zixu Mao ◽  
Qian Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Mitochondrial Homeostasis ◽  
New Findings ◽  
Novel Therapeutic Strategies ◽  
Chaperone Mediated Autophagy

Parkinson’s disease (PD), a complex neurodegenerative disorder, is pathologically characterized by the formation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial dysfunction is considered to be one of the most important causative mechanisms. In addition, dysfunction of chaperone-mediated autophagy (CMA), one of the lysosomal proteolytic pathways, has been shown to play an important role in the pathogenesis of PD. An exciting and important development is recent finding that CMA and mitochondrial quality control may be linked. This review summarizes the studies revealing the link between autophagy and mitochondrial function. Discussions are focused on the connections between CMA and mitochondrial failure and on the role of MEF2D, a neuronal survival factor, in mediating the regulation of mitochondria in the context of CMA. These new findings highlight the need to further explore the possibility of targeting the MEF2D-mitochondria-CMA network in both understanding the PD pathogenesis and developing novel therapeutic strategies.

scholarly journals Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson’s disease cohort

2019 ◽  
Author(s):  
O.E.E. Graham ◽  
T.L. Pitcher ◽  
Y. Liau ◽  
A.L. Miller ◽  
J.C. Dalrymple-Alford ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
New Zealand ◽  
Gaucher Disease ◽  
Nanopore Sequencing ◽  
Lysosomal Storage ◽  
Coding Region ◽  
Structural Variations ◽  
Sequencing Platform ◽  
Nanopore Dna Sequencing

AbstractIntroductionBi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson’s disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD.MethodWe examined amplicons encompassing the coding region of GBA (8.9kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation.ResultsWe detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C>T or p.(L335=), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants.ConclusionThis work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

The Lysosome and Nonmotor Symptoms: Linking Parkinson's Disease and Lysosomal Storage Disorders

2020 ◽  
Vol 35 (12) ◽  
pp. 2150-2155
Author(s):  
Shani Blumenreich ◽  
Bethan J. Jenkins ◽  
Or B. Barav ◽  
Ivan Milenkovic ◽  
Anthony H. Futerman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Nonmotor Symptoms ◽  
Storage Disorders
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