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Annals of Clinical and Translational... Jun 2023LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence... (Review)
Review
LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.
Topics: Humans; Parkinson Disease; Lewy Bodies; Alzheimer Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
PubMed: 37021623
DOI: 10.1002/acn3.51776 -
Molecular Neurodegeneration May 2023Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing.
METHODS
Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD.
RESULTS
Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons.
CONCLUSIONS
Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.
Topics: Humans; Parkinson Disease; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Neuropathology; alpha-Synuclein
PubMed: 37173733
DOI: 10.1186/s13024-023-00622-7 -
Biomolecules Oct 2021Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic... (Review)
Review
Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.
Topics: Biomarkers; Dopaminergic Neurons; Humans; Lewy Bodies; Mitochondria; Neuroinflammatory Diseases; Parkinson Disease; Protein Aggregates; Proteostasis Deficiencies; Reactive Oxygen Species; alpha-Synuclein
PubMed: 34680141
DOI: 10.3390/biom11101508 -
Journal of Parkinson's Disease 2023The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from... (Review)
Review
The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Lewy Body Disease; Lewy Bodies; Nerve Degeneration; Biomarkers; Prodromal Symptoms; Biological Products
PubMed: 37066922
DOI: 10.3233/JPD-225111 -
Nature Protocols Sep 2014This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found...
Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates.
This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found in Parkinson's disease brains and other synucleinopathies. This model allows investigation of aggregate formation, their impact on neuron function, and development of therapeutics. Addition of preformed fibrils (PFFs) synthesized from recombinant α-syn to neurons seeds the recruitment of endogenous α-syn into aggregates characterized by detergent insolubility and hyperphosphorylation. Aggregate formation follows a lag phase of 2-3 d, followed by formation in axons by days 4-7, spread to somatodendritic compartments by days 7-10 and neuron death ~14 d after PFF addition. Here we provide methods and highlight the crucial steps for PFF formation, PFF addition to cultured hippocampal neurons and confirmation of aggregate formation. Neurons derived from various brain regions from nontransgenic and genetically engineered mice and rats can be used, allowing interrogation of the effect of specific genes on aggregate formation.
Topics: Animals; Cell Culture Techniques; Fluorescent Antibody Technique; Immunoblotting; Lewy Bodies; Mice; Models, Biological; Multiprotein Complexes; Neurites; Rats; alpha-Synuclein
PubMed: 25122523
DOI: 10.1038/nprot.2014.143 -
Journal of the Anus, Rectum and Colon 2019We systematically reviewed literature regarding "Lewy body constipation", i.e., constipation due to Lewy body diseases (LBD), with minimal neurologic symptoms.... (Review)
Review
We systematically reviewed literature regarding "Lewy body constipation", i.e., constipation due to Lewy body diseases (LBD), with minimal neurologic symptoms. Epidemiology and pathology studies showed that LBD can start with constipation alone, mostly due to neuronal loss and appearance of Lewy bodies in the myenteric plexus. Because LBD significantly increases with age, "Lewy body constipation" may also increase with age. Neuroimaging methods such as metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter (DAT) scan provide a way to detect "Lewy body constipation." Key for "Lewy body constipation" includes minimal non-motor features such as REM sleep behavior disorder (night talking). Add-on therapy may be required to ameliorate constipation in patients. Diagnosis is not always easy; therefore, collaboration of gastroenterologists and neurologists is highly recommended to maximize patients' quality of life. In conclusion, "Lewy body constipation" might become a distinct category among geriatric constipation, regarding patients' follow-up and their management.
PubMed: 31559362
DOI: 10.23922/jarc.2018-022 -
Neuroscience Letters Sep 2019Over 20 years ago, the synaptic protein α-synuclein was identified as the primary component of the Lewy bodies (LBs) that are a sine qua non of Parkinson's disease... (Review)
Review
Over 20 years ago, the synaptic protein α-synuclein was identified as the primary component of the Lewy bodies (LBs) that are a sine qua non of Parkinson's disease (PD). Since that time, extensive research has demonstrated that α-synuclein pathology is not only a hallmark of PD, but can also cause neuronal dysfunction and death. Detailed staging of α-synuclein pathology in the brains of patients has revealed a progressive pattern of pathology that correlates with the symptoms of disease. Early in the disease course, PD patients exhibit motor dysfunction, and α-synuclein pathology at this stage is primarily found in regions controlling motor function. At later stages of disease as patients' cognitive function deteriorates, α-synuclein pathology can be found in cortical structures responsible for higher cognitive processing. The stereotypical progression of α-synuclein pathology through the brain over time suggests that there may be a physical transmission of pathological α-synuclein from one area of the brain to another. The transmission hypothesis posits that an initial seed of pathological α-synuclein in one neuron may be released and taken up by another vulnerable neuron and thereby initiate pathological misfolding of α-synuclein in the recipient neuron. In recent years, convergent evidence from various studies has indicated that pathological protein transmission can occur in the human brain. Cell and animal models based on the transmission hypothesis have shown not only that pathological α-synuclein can be transmitted from cell-to-cell, but that this pathology can lead to neuronal dysfunction and degeneration. The α-synuclein transmission hypothesis has profound implications for treatment of what is currently an intractable neurodegenerative disease. In this review, we explore the evidence for cell-to-cell transmission of pathological α-synuclein, the current understanding of how pathological α-synuclein can move to a new cell and template misfolding, and the therapeutic implications of α-synuclein transmission.
Topics: Animals; Brain; Glymphatic System; Humans; Lewy Bodies; Parkinson Disease; Synucleinopathies; alpha-Synuclein
PubMed: 31170426
DOI: 10.1016/j.neulet.2019.134316 -
Neurologic Clinics May 2017Dementia syndromes associated with Lewy bodies are subdivided into dementia with Lewy bodies (DLB), an underdiagnosed cause of dementia in the elderly, and Parkinson... (Review)
Review
Dementia syndromes associated with Lewy bodies are subdivided into dementia with Lewy bodies (DLB), an underdiagnosed cause of dementia in the elderly, and Parkinson disease with dementia (PDD), cognitive impairment appearing in people diagnosed with Parkinson disease. Their neuropathologic substrates are the widespread distribution of aggregates of the protein α-synuclein in neurons in cortical brain regions, accompanied by variable Alzheimer pathology. Clinical features of DLB and PDD include distinctive changes in cognition, behavior, movement, sleep, and autonomic function. Diagnostic criteria for DLB and PDD incorporate these features. Current treatment options for DLB and PDD are symptomatic.
Topics: Brain; Disease Management; Humans; Lewy Body Disease; alpha-Synuclein
PubMed: 28410662
DOI: 10.1016/j.ncl.2017.01.004 -
Cell Death & Disease Mar 2023Although the discovery of the critical role of α-synuclein (α-syn) in the pathogenesis of Parkinson's disease (PD) is now twenty-five years old, it still represents a... (Review)
Review
Although the discovery of the critical role of α-synuclein (α-syn) in the pathogenesis of Parkinson's disease (PD) is now twenty-five years old, it still represents a milestone in PD research. Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of α-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting α-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.
Topics: Humans; alpha-Synuclein; Inflammation; Lewy Bodies; Parkinson Disease; Synucleinopathies
PubMed: 36859484
DOI: 10.1038/s41419-023-05672-9 -
Proceedings of the National Academy of... Mar 2020Parkinson's disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs)....
Parkinson's disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces the key events leading to LB formation, including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, posttranslational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome, and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate therapeutics targeting α-syn aggregation and LB formation.
Topics: Animals; Autophagosomes; Humans; Lewy Bodies; Lysosomes; Mitochondria; Neurodegenerative Diseases; Neurons; Parkinson Disease; Transcriptome; alpha-Synuclein
PubMed: 32075919
DOI: 10.1073/pnas.1913904117