Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages

2011 ◽  
Vol 44 (2) ◽  
pp. 192-204 ◽  
Author(s):  
Silke Nuber ◽  
Elisabeth Petrasch-Parwez ◽  
Oscar Arias-Carrión ◽  
Leanie Koch ◽  
Zacharias Kohl ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Olfactory Neuron ◽  
Specific Expression ◽  
Conditional Model ◽  
Disease Stages ◽  
Early Parkinson’S Disease

scholarly journals Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 795
Author(s):  
Milos Stanojlovic ◽  
Jean Pierre Pallais ◽  
Catherine M. Kotz
Keyword(s):  
Physical Activity ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Energy Expenditure ◽  
Transgenic Animal ◽  
Alpha Synuclein ◽  
Behavioral Disturbances ◽  
Spontaneous Physical Activity ◽  
Exploratory Locomotion ◽  
Early Parkinson’S Disease

Aside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesized that Parkinson’s-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson’s, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson’s disease pathology. This study implicates the involvement of orexin in early Parkinson’s-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson’s disease symptomology.

scholarly journals High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Marco J. Russo ◽  
Christina D. Orru ◽  
Luis Concha-Marambio ◽  
Simone Giaisi ◽  
Bradley R. Groveman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Diagnosis ◽  
Diagnostic Performance ◽  
De Novo ◽  
Alpha Synuclein ◽  
Diagnostic Tools ◽  
Dat Spect ◽  
Progression Markers ◽  
Early Parkinson’S Disease

AbstractAlpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods.

scholarly journals Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

PLoS ONE ◽  
2011 ◽  
Vol 6 (12) ◽  
pp. e28032 ◽  
Author(s):  
Christopher B. Forsyth ◽  
Kathleen M. Shannon ◽  
Jeffrey H. Kordower ◽  
Robin M. Voigt ◽  
Maliha Shaikh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intestinal Permeability ◽  
Alpha Synuclein ◽  
Endotoxin Exposure ◽  
Early Parkinson’S Disease

scholarly journals Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3565-3579 ◽  
Author(s):  
Yaping Chu ◽  
Scott Muller ◽  
Adriana Tavares ◽  
Olivier Barret ◽  
David Alagille ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopamine Transporter ◽  
Lewy Body ◽  
Alpha Synuclein ◽  
Lewy Body Pathology ◽  
Nigrostriatal Degeneration ◽  
Early Parkinson’S Disease

See Dehay and Bezard (doi:10.1093/brain/awz329) for a scientific commentary on this article. Intrastriatal injections of fibrillar α-synuclein in rodents have been shown to induce a Parkinson’s disease-like spreading of Lewy body pathology. Chu et al. inject exogenous α-synuclein pre-formed fibrils into the putamen of non-human primates, and observe spreading of pathology, nigrostriatal degeneration, and dopamine transporter upregulation indicative of early Parkinson’s disease.

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