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

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.

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Chemical and Biological Molecules Involved in Differentiation, Maturation, and Survival of Dopaminergic Neurons in Health and Parkinson’s Disease: Physiological Aspects and Clinical Implications

Biomedicines ◽

10.3390/biomedicines9070754 ◽

2021 ◽

Vol 9 (7) ◽

pp. 754

Author(s):

Giulia Gaggi ◽

Andrea Di Credico ◽

Pascal Izzicupo ◽

Giovanni Iannetti ◽

Angela Di Baldassarre ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Potential Role ◽

High Efficiency ◽

Biological Molecules ◽

Alternative Approach ◽

Non Coding Rnas ◽

Set Up

Parkinson’s disease (PD) is one of the most common neurodegenerative disease characterized by a specific and progressive loss of dopaminergic (DA) neurons and dopamine, causing motor dysfunctions and impaired movements. Unfortunately, available therapies can partially treat the motor symptoms, but they have no effect on non-motor features. In addition, the therapeutic effect reduces gradually, and the prolonged use of drugs leads to a significative increase in the number of adverse events. For these reasons, an alternative approach that allows the replacement or the improved survival of DA neurons is very appealing for the treatment of PD patients and recently the first human clinical trials for DA neurons replacement have been set up. Here, we review the role of chemical and biological molecules that are involved in the development, survival and differentiation of DA neurons. In particular, we review the chemical small molecules used to differentiate different type of stem cells into DA neurons with high efficiency; the role of microRNAs and long non-coding RNAs both in DA neurons development/survival as far as in the pathogenesis of PD; and, finally, we dissect the potential role of exosomes carrying biological molecules as treatment of PD.

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

Cells ◽

10.3390/cells10123547 ◽

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.

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Role of Genes and Treatments for Parkinson’s Disease

The Open Biology Journal ◽

10.2174/1874196702008010047 ◽

2020 ◽

Vol 8 (1) ◽

pp. 47-65

Author(s):

Falaq Naz ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Treatment Strategies ◽

Number Of Genes ◽

Permanent Cure

Parkinson’s Disease (PD) is a complex neurodegenerative disorder that mainly results due to the loss of dopaminergic neurons in the substantia nigra of the midbrain. It is well known that dopamine is synthesized in substantia nigra and is transported to the striatum via nigrostriatal tract. Besides the sporadic forms of PD, there are also familial cases of PD and number of genes (both autosomal dominant as well as recessive) are responsible for PD. There is no permanent cure for PD and to date, L-dopa therapy is considered to be the best option besides having dopamine agonists. In the present review, we have described the genes responsible for PD, the role of dopamine, and treatment strategies adopted for controlling the progression of PD in humans.

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Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

10.21203/rs.3.rs-1207279/v1 ◽

2022 ◽

Author(s):

Min Hyung Seo ◽

Sujung Yeo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cell Loss ◽

Alpha Synuclein ◽

Mice Model ◽

Dopaminergic Cell ◽

The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

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Genetics of Parkinson's disease

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2004.6.3/tgasser ◽

2004 ◽

Vol 6 (3) ◽

pp. 295-301

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Free Radicals ◽

Dopaminergic Neurons ◽

Genetic Factors ◽

Point Mutations ◽

Degradation Pathway ◽

Molecular Pathways ◽

Mitochondrial Energy Metabolism

The etiology of most cases of Parkinson's disease (PD) remains unknown. In recent years, however, research has successfully focused on genetic factors contributing to the degeneration of dopaminergic neurons. Causative mutations have been identified in several monogenically inherited forms of the disease. Although these genetic forms of PD are usually rare, the gene discoveries are likely to identify molecular pathways that are also relevant in the sporadic disorder. These studies have led to the identification of (i) the central role of α-synuclein aggregation, secondary to either point mutations or an amplification of the α-synuclein gene; and (ii) the relevance of defects in the proteasomal protein degradation pathway in the molecular pathogenesis of recessive parkin-linked forms of PD. The recent discoveries of two additional recessive forms associated with mutations in the genes DJ-1 and PINK1 have brought the mitochondrial energy metabolism and the cell's defence against toxic free radicals into the focus of research.

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Neuron-Astrocyte Interactions in Parkinson’s Disease

Cells ◽

10.3390/cells9122623 ◽

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.

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Immune system and new avenues in Parkinson’s disease research and treatment

Reviews in the Neurosciences ◽

10.1515/revneuro-2018-0105 ◽

2019 ◽

Vol 30 (7) ◽

pp. 709-727 ◽

Cited By ~ 5

Author(s):

Ava Nasrolahi ◽

Fatemeh Safari ◽

Mehdi Farhoudi ◽

Afra Khosravi ◽

Fereshteh Farajdokht ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Neuronal Loss ◽

Disease Research ◽

Disease Modifying Therapies ◽

Progressive Neurodegeneration ◽

Disease Modifying ◽

Clinical Description ◽

Genetic And Environmental Factors

Abstract Parkinson’s disease (PD) is a progressive neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. However, although 200 years have now passed since the primary clinical description of PD by James Parkinson, the etiology and mechanisms of neuronal loss in this disease are still not fully understood. In addition to genetic and environmental factors, activation of immunologic responses seems to have a crucial role in PD pathology. Intraneuronal accumulation of α-synuclein (α-Syn), as the main pathological hallmark of PD, potentially mediates initiation of the autoimmune and inflammatory events through, possibly, auto-reactive T cells. While current therapeutic regimens are mainly used to symptomatically suppress PD signs, application of the disease-modifying therapies including immunomodulatory strategies may slow down the progressive neurodegeneration process of PD. The aim of this review is to summarize knowledge regarding previous studies on the relationships between autoimmune reactions and PD pathology as well as to discuss current opportunities for immunomodulatory therapy.

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Role of α-synuclein in neurodegeneration: implications for the pathogenesis of Parkinson's disease

Essays in Biochemistry ◽

10.1042/bse0560125 ◽

2014 ◽

Vol 56 ◽

pp. 125-135 ◽

Cited By ~ 8

Author(s):

Shun Yu ◽

Piu Chan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Experimental Studies ◽

Research Progress ◽

Pathogenic Role ◽

Normal Expression ◽

The Brain ◽

Recent Research Progress

α-Syn (α-synuclein) is a small soluble acidic protein that is extensively expressed in the nervous system. Genetic, clinical and experimental studies demonstrate that α-syn is strongly implicated in the pathogenesis of PD (Parkinson's disease). However, the pathogenic mechanism remains elusive. In the present chapter, we first describe the normal expression and potential physiological functions of α-syn. Then, we introduce recent research progress related to the pathogenic role of α-syn in PD, with special emphasis on how α-syn oligomers cause the preferential degeneration of dopaminergic neurons in the substantia nigra and the spreading of α-syn pathology in the brain of PD patients.

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Herbal Resources to Combat a Progressive & Degenerative Nervous System Disorder - Parkinson’s Disease

Current Drug Targets ◽

10.2174/1389450121999201013155202 ◽

2020 ◽

Vol 21 ◽

Author(s):

Bairong Shen ◽

Rajeev K. Singla ◽

Tanya Agarwal ◽

He Xuefei

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Natural Products ◽

Dopaminergic Neurons ◽

Symptomatic Treatment ◽

Neuroprotective Effects ◽

Chronic Disorder ◽

System Disorder ◽

Pro Inflammatory Cytokines

: Parkinson’s disease is one of the most common adult-onset, a chronic disorder involving neurodegeneration, pro-gressively leading to deprivation of dopaminergic neurons in substantia nigra, causing a subsequent reduction of dopa-mine levels in the striatum resulting in tremor, myotonia, and dyskinesia. Genetics and environmental factors are believed to be responsible for the onset of Parkinson’s disease. The exact pathogenesis of Parkinson's dis-ease is quite complicated and the present anti-Parkinson's disease treatments appear to be clinically insufficient. Comprehensive researches have demonstrated the use of natural products such as ginseng, curcumin, ashwa-gandha, baicalein, etc. for the symptomatic treatment of this disease. The neuroprotective effects exhibited by these natural products are mainly due to their ability to increase dopamine levels in the striatum, manage oxidative stress, mitochondrial dysfunction, glutathione levels, clear the aggregation of α-synuclein, induce the autophagy and de-crease the pro-inflammatory cytokines and lipid peroxidation. This paper reviews various natural product studies conducted by the scientists to establish the role of natural products (both metabolite extracts as well as pure metabolites) as adjunctive neuroprotective agents.

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