RETRACTED ARTICLE: Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

Abstract

BackgroundParkinson’s disease (PD) is a neurodegenerative disease characterized by intraneuronal Lewy Body (LB) aggregates composed of misfolded alpha-synuclein (α-syn). The spread of misfolded α-syn follows a typical pattern: starting in the olfactory bulb (OB) and the gut, this pathology is followed by the progressive invasion of misfolded α-syn to the posterior part of the brain. It is unknown whether the administration of human mutant alpha-synuclein (hm-α-syn, a human mutation which occurs in familial PD) into the OB of rats would trigger similar α-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD.Methodshm-α-syn was overexpressed in the OB of rats with an AAV injection. Then motor and non-motor symptoms of the SD rats were tested in different behavioral tasks following the AAV injection. In follow-up studies, pathological mechanisms of α-syn spread were explored at the histological, biochemical and micro-structure levels.ResultsThe experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection. 1) overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope. 2) The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra (SN) 12 weeks after AAV injection. This was consistent with decreased levels of the DA neurotransmitter. Importantly, behavioral dysfunctions were found that included olfactory impairment after 3 weeks, motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3) The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB, prefrontal cortex (PFC), hippocampus (Hip) and striatum caudate putamen (CPU) were decreased. 4) phosphorylated α-syn, at Ser-129 (pSer129), was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone, which was also found in the most of LB stained by the thioflavine S (ThS) in the SN field. 5) A marker of autophagy (LC3B) was increased in serval fields, which was colacolizated with a marker of apoptosis in the SN field.ConclusionsThese results demonstrate that expression of exogenous mutant α-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenic α-syn to adjacent fields. This method may be useful for establishing an animal model of prodromal PD.

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

“…Rather, it seems more probable that fibril sonication protocols explain the differences across studies, as stated above . Our findings also differ significantly from a recent report that olfactory bulb α‐synucleinopathy causes similar pathology as in prodromal PD , but their model was generated by α‐synuclein overexpression.…”

Alpha-synuclein detection in olfactory mouse bulbs in ontogenesis in vivo and in the organotypic culture

“…Отростки обонятельных нейронов образуют в гломерулах контакты с дендритами митральных клеток, аксоны которых, в свою очередь, формируют прямые проекции в переднее обонятельное ядро, моносинаптически связанное с областями древней, старой и новой коры [28]. Таким образом, нормальное распределение α-Syn согласуется с гипотезой «обонятельного пути» распространения его патологических агрегатов [29][30][31]. Проведенный нами анализ структуры эксплантатов ОЛ в эмбриональном и постнатальном периоде показывает, что жизнеспособность клеток и основные характеристики структуры нативных ОЛ после 24 часов культивирования сохраняются.…”

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

“…Viral gene therapy vectors specifically designed for NDD applications should be able to efficiently cross the blood-brain barrier (BBB), if delivered by iv infusion [44,49], and support an efficient transgene expression, regardless of aberrant cell signaling caused by the accumulation of toxic proteins or restoration of an autophagic state in neuronal cells [50]. For instance, vectors based on genomes of adeno-associated virus (AAV) [44,49,[51][52][53][54][55][56], lentivirus [57], type 1 herpes simplex virus [58], and Semliki Forest virus (SFV) [59] have been broadly used for neuron targeting. Extensive use of the above viruses in neuroscience is dictated by their natural ability to efficiently and selectively transduce and provide high transgene expression in neurons.…”