The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

Abstract

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence of α-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.

Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease

“…Recently, numerous groups reported the pathological mechanism of ␣-syn. The main pathological action of ␣-syn resulted from its oligomeric state or fibrillization, and this format can cause LB formation, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation, and finally DA neuron death (7,8). Another important pathological action of ␣-syn fibrils is its transmission among neurons via endocytosis, plasma membrane penetration, or exosome pathways, thus propagating the LB pathology to other brain regions thereby contributing to the progressiveness of PD (3, 9 -11).…”

Anα-cyanostilbene derivative for the enhanced detection and imaging of amyloid fibril aggregates

“…The ability to perform in situ assays to monitor the fibrillar aggregation of proteins is particularly advantageous, as key kinetic and mechanistic processes can be monitored in real-time 21,28,29 . Thus, we sought to monitor the real-time aggregation of RCM κ-casein, a well characterised amyloid-forming protein 51,52 , as well as the aggregation of the Ab1-42 and -synuclein proteins, which are associated with the pathogenesis of Alzheimer's and Parkinson's disease, respectively [53][54][55] . Interestingly, our results suggest that ASCP is more sensitive to oligomeric species formed early during aggregation as there tended to be an earlier and more pronounced increase in ASCP fluorescence observed when monitoring the aggregation of RCM κ-casein and Ab1-42 compared to ThT.…”

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

“…The disease then progresses upwards through the medulla, pontine tegmentum, midbrain, basal forebrain and the cerebral cortex affecting more vulnerable neurons in these structures. It is possible that the PD progression is mediated by the spread and seeding of α-synuclein inclusions between neurons in a so called prion-like fashion (10,11). PD pathology seems to start in the olfactory structures and the dorsal nerve and a hypothesis, the "dual theory", is that an unknown neurotropic pathogen enters the nose and/or the gut and spreads via olfactory pathways and via the enteric plexus and preganglionic vagal fibers to the brain (12)(13)(14).…”