scholarly journals Parkinson's Disease: Leucine-Rich Repeat Kinase 2 and Autophagy, Intimate Enemies

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
José M. Bravo-San Pedro ◽  
Rubén Gómez-Sánchez ◽  
Elisa Pizarro-Estrella ◽  
Mireia Niso-Santano ◽  
Rosa A. González-Polo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Clinical Syndrome ◽  
Leucine Rich Repeat ◽  
Disease Etiology ◽  
Clinical Appearance ◽  
A Cell ◽  
Genetic And Environmental Factors

Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology.

Possible involvement of the relationship of LRRK2 and autophagy in Parkinson's disease

2012 ◽  
Vol 40 (5) ◽  
pp. 1129-1133 ◽  
Author(s):  
José M. Bravo-San Pedro ◽  
Rubén Gómez-Sánchez ◽  
Mireia Niso-Santano ◽  
Elisa Pizarro-Estrella ◽  
Rosa A. González-Polo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Clinical Appearance ◽  
Disease Mutations ◽  
A Cell ◽  
Nigral Degeneration ◽  
Relationship Of

PD (Parkinson's disease) is a neurodegenerative disorder caused by loss of dopamine-generating cells in the substantia nigra. The implication of genetic factors in the aetiology of PD has an essential importance in our understanding of the development of the disease. Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene cause late-onset PD with a clinical appearance indistinguishable from idiopathic PD. Moreover, LRRK2 has been associated with the process of autophagy regulation. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damaged proteins and cytoplasmic organelles. In the present paper, we discuss the role of LRRK2 in autophagy, and the importance of this relationship in the development of nigral degeneration in PD.

scholarly journals Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Bin Li ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
Yali Xie ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Age At Onset ◽  
Genetic Data ◽  
Genome Wide Association Studies ◽  
Onset Age ◽  
Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

scholarly journals Novel Insights on Genetic and Environmental Factors in Parkinson's Disease from a regional Swedish Case-Control Cohort

2021 ◽  
Author(s):  
Kajsa Brolin ◽  
Sara Bandres Ciga ◽  
Cornelis Blauwendraat ◽  
Hakan Widner ◽  
Per Odin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Factors ◽  
Environmental Exposures ◽  
Case Control ◽  
Risk Haplotype ◽  
Control Cohort ◽  
Disease Etiology ◽  
Continental Scale ◽  
Genetic And Environmental Factors

BACKGROUND: Risk factors for Parkinson's disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology. OBJECTIVE: We aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort. METHODS: PD patients (n=929) and matched population-based controls (n=935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores. RESULTS: The cohort is a representative PD case-control cohort (64% men, mean age at diagnosis = 67 years, median Hoehn and Yahr score = 2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we identified a potential novel, population-specific PD risk variant in the PLPP4 locus (rs12771445) along with a risk haplotype in the region. CONCLUSIONS: This work provides an in-depth description of a new PD case-control cohort from southern Sweden in which we identified a potential novel PD risk locus, PLPP4. Replication studies are needed to determine whether the PLPP4 locus is associated with PD in Sweden, and on a global scale.

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 Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

2020 ◽  
Author(s):  
Bernabe I. Bustos ◽  
Dimitri Krainc ◽  
Steven J. Lubbe ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Genetic Component ◽  
Genetic Risk Assessment ◽  
Whole Exome

ABSTRACTParkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

scholarly journals Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

2020 ◽  
pp. 1-22
Author(s):  
Anne-Marie Castonguay ◽  
Claude Gravel ◽  
Martin Lévesque
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Passive Immunization ◽  
Lewy Bodies ◽  
Gene Mutations ◽  
Alpha Synuclein ◽  
Multiple Sources ◽  
Immunization Strategies ◽  
A Cell

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

Genetic Insights into Early-onset Parkinson’s Disease

US Neurology ◽  
2010 ◽  
Vol 06 (01) ◽  
pp. 41
Author(s):  
Roy N Alcalay ◽  
Cheryl Waters ◽  
◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Early Onset ◽  
Late Onset ◽  
Positive Family History ◽  
Disease Onset ◽  
Leucine Rich Repeat ◽  
Strong Family History ◽  
Early Onset Parkinson’S Disease

Early-onset Parkinson’s disease (EOPD) is defined as disease onset before 40 or 50 years of age. The clinical characteristics of EOPD are very similar to those of late-onset PD, but dystonia is more often a presenting symptom, dementia is rare, and disease progression may be slower. Mutations in several genes have been described in cases with EOPD, often with strong family history, including mutations in α-synuclein (SNCA),DJ-1, PTEN-induced kinase-1 (PINK-1), andATP13A2. However, the most common mutations identified in EOPD are in Parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2), and glucocerebrosidase (GBA). With the exception ofSNCAandATP13A2carriers, mutation carriers are often indistinguishable from non-carriers. Large series of EOPD cases that are not ascertained by family history estimate mutation frequency at 4–16%. Given that the frequency of positive family history is much higher, we believe that many genetic risk factors are yet to be discovered.

scholarly journals Pesticides and Parkinson’s Disease

2001 ◽  
Vol 1 ◽  
pp. 207-208 ◽  
Author(s):  
Todd B. Sherer ◽  
Ranjita Betarbet ◽  
J. Timothy Greenamyre
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Selective Death ◽  
Underlying Mechanisms ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

scholarly journals Integration of functional genomics data to uncover cell type-specific pathways affected in Parkinson's disease

2021 ◽  
Author(s):  
Viola Volpato
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Biological Information ◽  
Cell Type ◽  
Risk Variants ◽  
Cell Type Specific

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.

scholarly journals DOPA-sparing strategy in the treatment of young onset Parkinson’s disease

2016 ◽  
Vol 7 (01) ◽  
pp. 67-69 ◽  
Author(s):  
Abdul Qayyum Rana ◽  
Mohamad Saleh ◽  
Muhammad Saad Yousuf ◽  
Wasim Mansoor ◽  
Syed Hussaini ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorder ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Retrospective Chart Review ◽  
Cross Sectional Study ◽  
Community Based ◽  
Cross Sectional ◽  
Young Onset

ABSTRACT Context: Late onset Parkinson’s disease (LOPD) is a neurodegenerative disorder afflicting individuals of ages 60 and older. However, 5–10% of cases can begin earlier between the ages 20 to 40, and are classified as young onset Parkinson disease (YOPD). Aim: In turn, this study aims to observe the trend in the choice of drug administered to patients with both YOPD and LOPD, with particular emphasis on this trend in its relation to the practice background of the neurologist. Settings and Design: A cross-sectional study was conducted in a community based Parkinson’s disease and movement disorder clinic. Statistical Analysis Used: Using a retrospective chart review data was obtained and analysed. Results: The results showed that 83% of general neurologists prescribed levodopa to their patients with YOPD, whereas movement-disorder specialists took a different approach altogether. They opted not to use levodopa and, in its stead, prescribed a mixture of alternate drugs.

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