Reviewing α-Synuclein Aggregation in Parkinson's Disease

Like other neurodegenerative conditions, Parkinson's disease is accompanied by the growing presence of a protein aggregate in the brain. The α-synuclein associated with Parkinson's disease is one of the few proteins in the body that can misfold in ways that encourage other molecules of the same protein to also misfold, this dysfunction spreading through tissue over time, creating solid protein aggregates that are toxic to cells or provoke inflammatory reactions in brain tissue. Targeting these aggregates is at present an active area of research, albeit not as far advanced towards the clinic as is the case for targeting the different forms of protein aggregates found in Alzheimer's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that falls under the category of synucleinopathy. PD is characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region and the decrease in dopamine levels. Possibly, PD leads to the loss of terminal ends of striatum, which occurs before the neuronal loss in SNpc and; it seems to be more significant in disease pathogenesis. About 95% of PD cases are sporadic with no genetic linkage. Mostly, PD has its mean age of onset at 55 years with increased incidences with aging.

The most pathological hallmark of PD is Lewy bodies (LB). Lewy bodies are intraneuronal inclusions that contain immunoreactive alpha-synuclein aggregates which may also contain various neurofilament proteins as well as proteins involved in proteolysis such as ubiquitin. Predominantly, the cell death is caused by disruption of nuclear membrane integrity and release of alpha synuclein aggregation promoting nuclear factors like histones. Alpha synuclein may spread to other cells by direct or indirect means once aggregation starts. When compared with unaffected normal individuals, around 50-70% of neurons are lost in this region, at the time of death in patients with PD. Some studies suggest that LBs are the cell's defensive mechanism to prevent intracellular protein aggregate accumulation, while other studies suggest LBs to have a pathogenic role in PD.

Presently, there are no effective therapeutics contrived for PD. A prudent way to effectively alleviate PD would be to target one of its crucial causatives, alpha-synuclein. Recently, various therapeutic strategies have been formulated, to encumber alpha-synuclein's toxic effect. One such strategy would be to control transmission by blocking alpha-synuclein receptors. LAG3-directed antibodies were reported to substantially regulate aberrant alpha-synuclein induced toxicity. Concurrently, silencing alpha-synuclein expression in mouse and rat brain models through shRNA and siRNA was also reported. Further, the oligomer regulator Anle138b was able to hinder the synthesis and accumulation of alpha-synuclein oligomers. Additionally, numerous small molecule-based inhibitors have been elucidated to impede alpha-synuclein aggregation.


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