Alpha-synuclein and the Movement Pathway Under Healthy Conditions

Parkinson’s disease (PD) has been known and recognized for more than 200 years, and yet a lot of the small details regarding the disease and its progression are still unknown. Great strides have been made over the past 30 years towards reaching more conclusive answers about the pathology of this disease, as well as the normal healthy state functions of the players involved in Parkinson’s disease.

Substantia Nigra and Movement

The substantia nigra is the area of the brain that is most heavily effected by degeneration due to Parkinson’s disease. The substantia nigra is situated in the midbrain posterior to the crus cerebri fibers of the cerebral peduncle. Although it is present anatomically within the brain, it is considered to be a part of the basal ganglia.19The SN itself is split into two halves: pars reticularis and pars compacta. Pars reticularis is anterior to pars compacta in the cerebellar peduncles, and is made up of GABAergic neurons. This part of the SN is not typically associated with Parkinson’s disease. Pars compacta however, is the section involved with PD. This section is posterior and medial to pars reticulate, and is actually made up primarily of dopaminergic neurons. These are the types of neurons that are effected and killed during Parkinson’s disease pathogenesis, as their death leads to the loss of dopamine associated with PD symptoms.1920It is well understood that a huge role of the pars compacta of the substantia nigra, and the basal ganglia at large is its involvement in movement. The participation of the pars compacta in this process revolves around its relationship to the striatum through efferent fibers. Dopaminergic cells in the pars compacta will release dopamine neurotransmitter to be sent to the dopamine receptors within the striatum. There are two types of receptors: D1 and D2. D1 receptors are excitatory receptors, and the binding of dopamine here results in the activation of the direct movement pathway, and allows for movements to occur. The D2 receptors are inhibitory receptors that are a part of the indirect pathway. Upon dopamine binding, inhibition of the indirect pathway occurs, and results in the promotion of further movements. These pathways and their involvement with dopamine make it clear how the destruction of dopaminergic neurons within pars compacta can lead to the motor function deficiency of Parkinson’s disease.19

Figure highlighting the impact of alpha-synuclein aggregation on the movement pathway in comparison to the healthy state. https://www.annualreviews.org/doi/pdf/10.1146/annurev-pathol-011110-130242

Alpha-synuclein structure

            Thanks to the initial identification of the SNCA gene’s involvement in genetic PD pathogenesis and the presence of alpha-synuclein within Lewy bodies of PD patients, we now know that the method by which the dopaminergic neurons are destroyed is through the formation of Lewy bodies and aggregation of alpha-synuclein within the DA neurons. Because of this, the importance of understanding the normal function of alpha-synuclein has increased drastically in the past couple of decades. Although what is presently known about the protein’s function is not complete, more and more evidence for its neuronal role is presented every year.21

            In terms of structure, alpha-synuclein is a 14 kD,140 amino acid protein, and is a membrane of the synuclein family that also includes beta and gamma-synuclein. In its native state, it is known to be in a monomeric, soluble, and disordered conformation. Upon the binding of alpha-synuclein to structures such as lipid membranes, its conformation can be changed depending on what role it is performing.2223For example, alpha-syn forms alpha-helical structures upon binding to negatively charged lipids, and can also form beta sheet structures following prolonged periods of incubation. The protein itself is made up of three very distinct regions: an amino terminus with apoliporotein lipid binding motifs (amino acids 1-60), a hydrophobic center region (61-95), and an acidic carboxyl terminus (96-140). While this information is known, the specifics of alpha-syn’s native state are still somewhat unknown and have not been entirely confirmed.22

PDB structure of alpha-synuclein in its native, monomeric state. Highlighted in green is Ser129, which is often found to be phosphorylated in the oligomeric state.

Alpha-synuclein Function

            Along these same lines, the exact function of alpha-synuclein within the dopaminergic neurons is unclear. With that being said, many researchers have reached a bit of a consensus of its likely function based off of what we know about its structure and its localization within DA neurons. Alpha-syn monomers are typically found in abundance near the synapses of DA neuron, suggesting an involvement in synaptic trafficking and vesicle formation. A study in 2010 found that alpha-synuclein acts as a required chaperone for the maintenance of continuous SNARE complex assembly by binding directly to the SNARE-protein synaptobrevin-2 at its C-terminus, and binding to phospholipids at its N-terminus. The SNARE complex allows for proper neurotransmitter release by forming a tightly coordinated membrane fusion machinery. Immunoprecipitation experiments of SNARE complexes from mouse brain homogenates found that alpha-syn co-immunoprecipitated with it, displaying its involvement in the SNARE process. Additionally, alpha-syn KO in mice leads to an age-dependent decrease in SNARE complex assembly, thus confirming the requirement of alpha-synuclein to maintain normal SNARE complex assembly, and the function of alpha-syn in synaptic trafficking.24

            A different study from 2013 also aimed to elucidate the molecular functions of synucleins, alpha-synuclein in particular. In order to do so, the authors used unbiased proteomics and found that upon the loss of synucleins, four different proteins responsible for sensing and generating membrane curvature (endophilin A1, endophilin B2, annexin A5, and synapsin IIb) are all upregulated. This finding suggests that the synuclein family likely functions in a similar manner. This is because the previously stated proteins share a lipid-binding amphipathic structure similar to synucleins. Additionally, different methods of microscopy were used to determine that monomeric, as opposed to a tetrameric conformation, alpha-synuclein is capable of generating membrane curvature.25

References

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