scholarly journals A Case of Parkinson’s Disease with No Lewy Body Pathology due to a Homozygous Exon Deletion in Parkin

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Krisztina Kunszt Johansen ◽  
Sverre Helge Torp ◽  
Matthew J. Farrer ◽  
Emil K. Gustavsson ◽  
Jan O. Aasly
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Diagnostic Criteria ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Homozygous Deletion ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Body Pathology ◽  
Deep Brain

Parkinson’s disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, good response to levodopa, and no other explanations of the syndrome. Earlier diagnostic criteria required autopsy for a definite diagnosis based on neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies and neurites. Here, we present a patient who developed parkinsonism around the age of 20, with an excellent response to levodopa who, at age 65, received bilateral STN deep brain stimulation (DBS). The patient died at age 79. The autopsy showed severe neuronal loss in the SN without any Lewy bodies in the brainstem or in the hemispheres. Genetic screening revealed a homozygous deletion of exon 3-4 in the Parkin gene. In this case report we discuss earlier described pathological findings in Parkin cases without Lewy body pathology, the current diagnostic criteria for PD, and their clinical relevance.

scholarly journals When Friendship Turns Sour: Effective Communication Between Mitochondria and Intracellular Organelles in Parkinson's Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Tsu-Kung Lin ◽  
Kai-Jung Lin ◽  
Kai-Lieh Lin ◽  
Chia-Wei Liou ◽  
Shang-Der Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stress Responses ◽  
Redox Homeostasis ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Physical Contact ◽  
Substantia Nigra Pars Compacta ◽  
Intracellular Organelles ◽  
Pleiotropic Functions

Parkinson's disease (PD) is a complex neurodegenerative disease with pathological hallmarks including progressive neuronal loss from the substantia nigra pars compacta and α-synuclein intraneuronal inclusions, known as Lewy bodies. Although the etiology of PD remains elusive, mitochondrial damage has been established to take center stage in the pathogenesis of PD. Mitochondria are critical to cellular energy production, metabolism, homeostasis, and stress responses; the association with PD emphasizes the importance of maintenance of mitochondrial network integrity. To accomplish the pleiotropic functions, mitochondria are dynamic not only within their own network but also in orchestrated coordination with other organelles in the cellular community. Through physical contact sites, signal transduction, and vesicle transport, mitochondria and intracellular organelles achieve the goals of calcium homeostasis, redox homeostasis, protein homeostasis, autophagy, and apoptosis. Herein, we review the finely tuned interactions between mitochondria and surrounding intracellular organelles, with focus on the nucleus, endoplasmic reticulum, Golgi apparatus, peroxisomes, and lysosomes. Participants that may contribute to the pathogenic mechanisms of PD will be highlighted in this review.

scholarly journals MicroRNAs: Game Changers in the Regulation of α-Synuclein in Parkinson’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Liang Zhao ◽  
Zhiqin Wang
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Noncoding Rnas ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Substantia Nigra Pars Compacta ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Its neuropathological hallmarks include neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies containing aggregates of α-synuclein (α-syn). An imbalance between the rates of α-syn synthesis, aggregation, and clearance can result in abnormal α-syn levels and contribute to the pathogenesis of PD. MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs (∼22 nucleotides) that have recently emerged as key posttranscriptional regulators of gene expression. In this review, we summarize the functions of miRNAs that directly target α-syn. We also review miRNAs that indirectly impact α-syn levels or toxicity through different pathways, including those involved in the clearance of α-syn and neuroinflammation.

Associations of Alzheimer’s Disease Neuropathologic Changes with Clinical Presentations of Parkinson’s Disease

2021 ◽  
pp. 1-7
Author(s):  
Qiang Tong ◽  
Liam Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Neuronal Loss ◽  
Clinical Information ◽  
Clinical Phenotypes ◽  
Lewy Body Pathology ◽  
The Impact

Background: Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the two most prevalent neurodegenerative diseases associated with age. Pathological studies have shown that these two diseases share a certain degree of neuropathological overlap. AD neuropathologic change contributes to cognitive impairment in PD. However, the impact of AD pathology on other clinical phenotypes in PD remains largely unknown. Objective: Herein we aimed to assess the impact of co-occurring AD neuropathologic change on the clinical phenotypes of PD. Methods: We examined 46 autopsy brains of PD patients and available clinical information to retrospectively assess the effects of comorbid AD pathology on dementia, hallucinations, and dyskinesia commonly seen in advanced PD. Results: AD neuropathology significantly increased the risk of hallucinations and dementia, but not dyskinesia in PD patients. Surprisingly, diffuse Lewy body pathology, but not AD pathology, was associated with the occurrence of dementia and hallucinations. Most importantly, we reported that the severity of neuronal loss in the locus coeruleus (LC), but not the severity of neuronal loss in the substantia nigra (SN), was associated with the occurrence of dyskinesia in advanced PD patients, while neither Lewy body scores in SN nor LC had significant effects. Conclusion: We show for the first time that neuronal loss in LC contributes to dyskinesia. Understanding the relationships between the two distinct pathologies and their relevant clinical phenotypes will be crucial in the development of effective disease-modifying therapies for PD.

scholarly journals DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology

Brain ◽  
2016 ◽  
Vol 139 (6) ◽  
pp. 1680-1687 ◽  
Author(s):  
Ricardo Taipa ◽  
Conceição Pereira ◽  
Inês Reis ◽  
Isabel Alonso ◽  
António Bastos-Lima ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Lewy Body ◽  
Single Case ◽  
Neuronal Loss ◽  
Poor Response ◽  
Therapeutic Interventions ◽  
Lewy Body Pathology

Abstract Mutations in DJ-1 (encoded by PARK7) are a very rare cause of early-onset recessive Parkinson’s disease. We describe a patient with early-onset parkinsonism, starting at the age of 22, with poor response to levodopa and additional features in progression (dystonia, pyramidal signs and dementia), who died when he was 49 years old. The neuropathological study showed severe substantia nigra and locus coeruleus neuronal loss, with diffuse Lewy body pathology (Lewy bodies, aberrant neurites, grain-like structures, spheroids and scattered glial pathology). Genetic analysis revealed a novel c.515T > A; p.L172Q mutation in the PARK7 gene. To evaluate the pathogenicity of this new mutation we explored DJ-1 expression levels in vitro showing a massive reduction in DJ-1 protein levels due to a highly unstable and rapidly degraded L172Q mutant. DJ-1 immunohistochemistry of brain tissue revealed no staining in our case. This is the first neuropathological report of a brain from DJ-1-linked parkinsonism that, although based on a single case study, suggests that DJ-1 mutations are causative of α-synucleinopathy. These results can help in the understanding of Parkinson’s disease pathophysiology, promote research studies to increase the knowledge on the pathways involved in the neurodegeneration process, and pave the way for new therapeutic interventions.

scholarly journals The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 804
Author(s):  
Luca Magistrelli ◽  
Elena Contaldi ◽  
Cristoforo Comi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Main Component ◽  
The Impact

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

“I See Them Sitting on My Bed, Doctor”

2016 ◽  
Author(s):  
Susan H. Fox ◽  
Marina Picillo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Body Burden ◽  
The Other ◽  
Lewy Body Pathology ◽  
Over Time

Many movement disorders specialists would consider dementia with Lewy bodies to be on one end of a spectrum of presentations associated with Lewy body pathology. Parkinson’s disease with preserved cognition sits at the other end of the spectrum, and over time it can be associated with a greater cortical Lewy body burden and related cognitive impairment. It is unclear what determines to what degree cognitive impairment is involved in a given patient, and the arbitrary time-based division between Parkinson’s disease and dementia with Lewy bodies is imperfect, although it serves to help recognition of this group of patients in whom management needs to be appropriately tailored.

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

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