alpha-synuclein and dihydrotetrabenazine

Evidence suggests that synapses are affected first in Parkinson's disease (PD). Here, we tested the claim that pathological accumulation of α-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human α-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve α-synuclein levels sufficient to induce terminal pathology without significant loss of nigral neurons. We tested synaptic disruption in vivo by analyzing motor defects and binding of a positron emission tomography (PET) radioligand to the vesicular monoamine transporter 2, (VMAT2), [

Topics: alpha-Synuclein; Animals; Carbon Radioisotopes; Corpus Striatum; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Positron-Emission Tomography; Presynaptic Terminals; Rats; Rats, Transgenic; Substantia Nigra; Synapses; Tetrabenazine; Vesicular Monoamine Transport Proteins

Previous studies demonstrated decreased levels of DJ-1 and α-synuclein (αSYN) in human cerebrospinal fluid (CSF) in patients with Parkinson's disease (PD), but neither marker correlated with PD severity, raising the possibility that they may be excellent progression markers during early or preclinical phases of PD. Individuals carrying the leucine-rich repeat kinase 2 (LRRK2) gene mutation are at increased risk for PD, and the phenotype of LRRK2 patients is almost identical to sporadic PD. To determine whether dopaminergic dysfunction in the basal ganglia, as determined by positron emission tomography (PET) scans, correlates with CSF levels of DJ-1 and αSYN during preclinical stages, Luminex assays were used to analyze CSF samples from asymptomatic LRRK2 mutation carriers, along with carriers who presented with a clinical diagnosis of PD. The data revealed no statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and αSYN, except for a weak correlation between DJ-1 and methylphenidate binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate.

Topics: alpha-Synuclein; Biomarkers; Carbon Isotopes; Corpus Striatum; Dopamine; Female; Fluorodeoxyglucose F18; Humans; Intracellular Signaling Peptides and Proteins; Japan; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Luria-Nebraska Neuropsychological Battery; Male; Methylphenidate; Norway; Oncogene Proteins; Parkinson Disease; Positron-Emission Tomography; Protein Deglycase DJ-1; Protein Serine-Threonine Kinases; Statistics as Topic; Tetrabenazine; United States