Neuropathology and molecular diagnosis of Synucleinopathies

Koga, Shunsuke; Sekiya, Hiroaki; Kondru, Naveen; Ross, Owen A.; Dickson, Dennis W.

doi:10.1186/s13024-021-00501-z

Cited by 168 publications

(106 citation statements)

References 264 publications

(240 reference statements)

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…It is abundant in the brain, but also be found in the skin, heart, salivary glands, retina, gastrointestinal tract, and olfactory mucosa ( Ma et al, 2019b ). In brain, α-Syn is mainly found in neural cells of the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum, but it was also found in glia cells ( Braak et al, 2003 ; Koga et al, 2021 ). Oral mucosa cells may share common α-Syn expression pattern with neurons since it is derived from ectodermal tissue which is also the embryonic origin of CNS ( Paraskevaidi et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Oral Mucosa Derived α−Synuclein as a Potential Diagnostic Biomarker for Parkinson′s Disease

Zheng

Cai

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

BackgroundPathological α-synuclein (α-Syn) is not only exclusive to the central nervous system (CNS) in Parkinson’s disease (PD), but also extended to biofluids and peripheral tissues including oral cavity. Both oral mucosa and nervous system are derived from ectodermal tissue, and potentially share common disease-specific characteristics. Oral mucosal exfoliative cytology is a non-invasive technique, which is an easily acceptable for patients and ordinary people. The purpose of this study was to determine the abnormal accumulation of α-Syn in oral mucosa of PD patients and to learn the diagnostic utility of oral mucosa α-Syn for PD.MethodsThe oral mucosa samples were obtained from 57 patients with PD and 51 age-matched controls by cytological brush. Immunofluorescence analysis was used to investigate the presence and subcellular localization of α-Syn, phosphorylated α-Syn at Ser129 (pS129) and oligomeric α-Syn in the oral mucosa cells of PD patients and controls. Images taken as Z-stacks were analyzed for 3D reconstruction to visualize the α-Syn intracellular localization. Then, the concentrations of α-Syn, pS129, and oligomeric α-Syn in oral mucosa samples were measured using electrochemiluminescence assays.ResultsImmunofluorescence images revealed the increased α-Syn, pS129, and oligomeric α-Syn levels in oral mucosa cells of PD patients than age-matched controls. The intracellular distributions of α-Syn species were determine by Z-stack images with 3D reconstruction, and α-Syn was detected in both the nucleus and cytoplasm. However, pS129 was mainly located in the cytoplasm, and oligomeric α-Syn was highly expressed in the nucleus and perinuclear cytoplasm. The concentrations of three α-Syn species were significantly increased in the oral mucosa cell samples of PD patients than controls (α-Syn, p = 0.001; pS129, p = 0.002; oligomeric α-Syn, p = 0.013). In PD patients, the oral mucosa α-Syn and oligomeric α-Syn levels were significantly correlated with Hoehn-Yahr scales (α-Syn, r = 0.495, p = 0.001; oligomeric α-Syn, r = 0.324, p = 0.03). The area under curve (AUC) of ROC analysis using an integrative model including α-Syn, pS129, and oligomeric α-Syn for PD diagnosis was 0.749, with 66.7% sensitivity and 72.5% specificity.ConclusionThis study for the first time demonstrated increased expressions of α-Syn, pS129, and oligomeric α-Syn in oral mucosa cells from PD patients, which serve as useful and non-invasive PD diagnostic biomarkers.

show abstract

Section: Discussionmentioning

confidence: 99%

Oral Mucosa Derived α−Synuclein as a Potential Diagnostic Biomarker for Parkinson′s Disease

Zheng

Cai

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…In addition, more than 80 different proteins, membranes, lipids, and distorted organelles have also been identified in these aggregates [ 44 , 45 ]. There are two subtypes of LBs, the classical brainstem type and the cortical type, each with a different localization, as well as a different microstructure, which affects the likelihood of their identification during the neuropathology examination [ 46 ]. Since GBA1 -LBD shares essential histopathological features of LBD, the histopathological signature in GD-LBD could potentially provide insights into pathophysiology relevant to a larger group of affected patients.…”

Section: Neuropathology Of Gaucher-associated Parkinsonismmentioning

confidence: 99%

Neuropathological Features of Gaucher Disease and Gaucher Disease with Parkinsonism

Furderer

Hertz

Lopez

et al. 2022

IJMS

View full text Add to dashboard Cite

Deficient acid β-glucocerebrosidase activity due to biallelic mutations in GBA1 results in Gaucher disease (GD). Patients with this lysosomal storage disorder exhibit a wide range of associated manifestations, spanning from virtually asymptomatic adults to infants with severe neurodegeneration. While type 1 GD (GD1) is considered non-neuronopathic, a small subset of patients develop parkinsonian features. Variants in GBA1 are also an important risk factor for several common Lewy body disorders (LBDs). Neuropathological examinations of patients with GD, including those who developed LBDs, are rare. GD primarily affects macrophages, and perivascular infiltration of Gaucher macrophages is the most common neuropathologic finding. However, the frequency of these clusters and the affected anatomical region varies. GD affects astrocytes, and, in neuronopathic GD, neurons in cerebral cortical layers 3 and 5, layer 4b of the calcarine cortex, and hippocampal regions CA2–4. In addition, several reports describe selective degeneration of the cerebellar dentate nucleus in chronic neuronopathic GD. GD1 is characterized by astrogliosis without prominent neuronal loss. In GD-LBD, widespread Lewy body pathology is seen, often involving hippocampal regions CA2–4. Additional neuropathological examinations in GD are sorely needed to clarify disease-specific patterns and elucidate causative mechanisms relevant to GD, and potentially to more common neurodegenerative diseases.

show abstract

“…Initial studies attempted to validate the seeding activity of aSyn by comparing brain and CSF samples. Interestingly, the great majority of the studies using these assays with CSF samples displayed good performance (high accuracy, sensitivity and specificity) as a potential diagnostic tool for PD 163 . In one comparative study, two independent groups evaluating the same sample set using two different aSyn SAAs (PMCA and RT-QuIC) reported similar results, exhibiting high sensitivity and specificity values, reflected by an improved AUC (i.e., PMCA-AUC = 0.93 and RT-QuIC-AUC = 0.89) for the clinical diagnosis of PD 35 .…”

Section: Introductionmentioning

confidence: 99%

Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies

Magalhães

Lashuel

2022

npj Parkinsons Dis.

View full text Add to dashboard Cite

Parkinson’s disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10–15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.

show abstract

Neuropathology and molecular diagnosis of Synucleinopathies

Cited by 168 publications

References 264 publications

Oral Mucosa Derived α−Synuclein as a Potential Diagnostic Biomarker for Parkinson′s Disease

Oral Mucosa Derived α−Synuclein as a Potential Diagnostic Biomarker for Parkinson′s Disease

Neuropathological Features of Gaucher Disease and Gaucher Disease with Parkinsonism

Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies

Contact Info

Product

Resources

About