scholarly journals Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3547
Author(s):  
Srinivasa Reddy Bonam ◽  
Christine Tranchant ◽  
Sylviane Muller
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Cell Survival ◽  
Control Systems ◽  
Therapeutic Strategies ◽  
Cell Type ◽  
Potential Therapeutic Target ◽  
Cellular Components

Cellular quality control systems have gained much attention in recent decades. Among these, autophagy is a natural self-preservation mechanism that continuously eliminates toxic cellular components and acts as an anti-ageing process. It is vital for cell survival and to preserve homeostasis. Several cell-type-dependent canonical or non-canonical autophagy pathways have been reported showing varying degrees of selectivity with regard to the substrates targeted. Here, we provide an updated review of the autophagy machinery and discuss the role of various forms of autophagy in neurodegenerative diseases, with a particular focus on Parkinson’s disease. We describe recent findings that have led to the proposal of therapeutic strategies targeting autophagy to alter the course of Parkinson’s disease progression.

scholarly journals Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

2018 ◽  
Vol 79 (5-6) ◽  
pp. 256-265 ◽  
Author(s):  
Jinhua Chen ◽  
Ying Chen ◽  
Jiali Pu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Significant Role ◽  
Dopaminergic Neurons ◽  
Recent Progress ◽  
Therapeutic Agents ◽  
Leucine Rich Repeat ◽  
Potential Therapeutic Target ◽  
Genetic And Environmental Factors

Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

scholarly journals Neuron-Astrocyte Interactions in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2623
Author(s):  
Ikuko Miyazaki ◽  
Masato Asanuma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Therapeutic Strategies ◽  
Pathogenic Role ◽  
Waste Products ◽  
Disease Modifying Drugs ◽  
Dopaminergic Neurodegeneration ◽  
The Central Nervous System

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

scholarly journals The Emerging Role of Proteolysis in Mitochondrial Quality Control and the Etiology of Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Riya Shanbhag ◽  
Guang Shi ◽  
Jarungjit Rujiviphat ◽  
G. Angus McQuibban
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Quality Control ◽  
Future Studies ◽  
Cellular Processes ◽  
Different Types ◽  
Calcium Buffering

Mitochondria are highly dynamic organelles that are important for many diverse cellular processes, such as energy metabolism, calcium buffering, and apoptosis. Mitochondrial biology and dysfunction have recently been linked to different types of cancers and neurodegenerative diseases, most notably Parkinson’s disease. Thus, a better understanding of the quality control systems that maintain a healthy mitochondrial network can facilitate the development of effective treatments for these diseases. In this perspective, we will discuss recent advances on two mitochondrial quality control pathways: the UPS and mitophagy, highlight how new players may be contributing to regulate these pathways. We believe the proteases involved will be key and novel regulators of mitochondrial quality control, and this knowledge will provide insights into future studies aimed to combat neurodegenerative diseases.

scholarly journals Quality Control of Mitochondria in Parkinson's Disease (PD) Using ATP And Bradford Assays

2022 ◽  
Author(s):  
Al-Baraa Akram
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Dopaminergic Neurons ◽  
Complex Disease ◽  
Motor Impairment ◽  
Lewy Bodies ◽  
Protease Gene ◽  
Mitochondrial Quality Control

Abstract Parkinson's disease is a heterogeneous, multifactorial and often complex disease characterized by motor impairment due to the presence of Lewy bodies and prominent degeneration of dopaminergic neurons in the substantia nigra. Although the specific pathogenesis involving PD remains under investigation, mitochondrial dysfunction has been widely accepted as one of the major pathogenic pathways underlying the development of PD. Based on the hypothesis that depiction of HtrA2 (serine protease gene, mitochondrial precursor) might contribute to an increase in mitochondrial stress and transcriptional upregulation of the nuclear stress-response CHOP gene. The present study aimed to analyze through laboratory-based research the role of HtrA2 and CHOP in the transmission of stress signaling and the consequent activation of mitochondrial quality control in Parkinson's disease using ATP and Bradford assays.

scholarly journals Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications

2021 ◽  
Vol 12 ◽  
Author(s):  
Rosie Bell ◽  
Michele Vendruscolo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lipid Membranes ◽  
Lewy Bodies ◽  
Lewy Neurites ◽  
Post Translational Modifications ◽  
Therapeutic Tools ◽  
Cellular Components ◽  
The Impact

Parkinson's disease is characterised by the presence in brain tissue of aberrant inclusions known as Lewy bodies and Lewy neurites, which are deposits composed by α-synuclein and a variety of other cellular components, including in particular lipid membranes. The dysregulation of the balance between lipid homeostasis and α-synuclein homeostasis is therefore likely to be closely involved in the onset and progression of Parkinson's disease and related synucleinopathies. As our understanding of this balance is increasing, we describe recent advances in the characterisation of the role of post-translational modifications in modulating the interactions of α-synuclein with lipid membranes. We then discuss the impact of these advances on the development of novel diagnostic and therapeutic tools for synucleinopathies.

scholarly journals Association of a Common Genetic Variant with Parkinson’s Disease is Propagated through Microglia

2021 ◽  
Author(s):  
R. G. Langston ◽  
A. Beilina ◽  
X. Reed ◽  
A. B. Singleton ◽  
C. Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Basis ◽  
Genetic Variant ◽  
Induced Pluripotent Stem Cell ◽  
Cell Type ◽  
Common Genetic Variant ◽  
Human Frontal Cortex ◽  
Induced Pluripotent

AbstractStudies of the genetic basis of Parkinson’s disease (PD) have identified many disease-associated genetic variants, but the mechanisms linking variants to pathogenicity are largely unknown. PD risk is attributed to both coding mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene and to common non-coding variation upstream of the LRRK2 locus. Here we show that the influence of genotype at non-coding variant rs76904798 on LRRK2 expression is propagated specifically through microglia, in contrast to evaluations based on general rather than genotype-dependent expression. We find evidence of microglia-specific regulatory regions that may modulate LRRK2 expression using single nuclei sequencing analyses of human frontal cortex and confirm these results in a human induced pluripotent stem cell-derived microglia model. Our study demonstrates that cell type is an important consideration in interrogation of the role of non-coding variation in disease pathogenesis.

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