Dear Editor,

We read with great interest the article by Al-Mazidi et al. [1] titled “Plasma Levels of Alpha and Gamma Synucleins in Autism Spectrum Disorder: An Indicator of Severity.” The aetiology and pathophysiology of autism spectrum disorder (ASD) are multifactorial and complex, involving genetic, environmental, immune dysregulation, neuroinflammation, and oxidative stress factors. Several biomarkers for diagnosing the severity and evaluating the pathogenesis have been reported previously. Synucleins are a family of presynaptic small soluble proteins. Of the many different proteins in this family, such as α-synuclein, β-synuclein, and γ-synuclein, α-synuclein is the most widely studied [1] due to its important role in neurodegenerative diseases (termed synucleinopathies), including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The role of α-synuclein in neurodevelopmental conditions such as ASD has also been studied [1]. There are several controversies regarding the evaluation of α-synuclein in ASD based on its source, such as plasma or saliva, although its levels are known to be relevant to disease severity [1‒4]. Varying levels of α-synuclein in children with ASD compared to normal matched controls have been reported, with some conflictingly reporting increased and decreased plasma levels [1‒3]. These differences are again based on the source (plasma or saliva); the sample sizes of prior studies were small, and larger studies are required to shed light on these controversies. Logically, as α-synuclein is a neurotransmitter, improvement in the communication ability of any child should increase its release; however, its circulation in plasma and the relationship to its expression in saliva are yet to be ascertained.

While there are studies evaluating the levels and discrepancies of plasma α-synuclein levels in ASD versus normal children, no interventions have yet reported the beneficial manipulation of α-synuclein, except for a recent study reporting the benefits of administering a biological response modifier beta glucan (BRMG) [5]. In that study, BRMG consumption increased plasma α-synuclein, which correlated with a beneficial improvement in subjective and objective criteria including behaviour, CARS score [5], sleep pattern and quality, and plasma melatonin [6]. Therefore, an increase in α-synuclein levels should be considered beneficial. Furthermore, the mechanism of this increase was attributed to the clearing of aggregated α-synuclein from the neural components of the gut through the enhancement of natural killer cells by BRMGs [5]. Another point to consider is that α-synuclein can present in monomeric, oligomeric, and fibrillar conformations [7]. The fibril conformation has been identified as a pathogenic species in neurodevelopmental and neurodegenerative disorders; however, the role of the monomeric and oligomeric forms leading to the fibril form has not yet been elucidated [7]. However, if this is the case, the higher circulating levels of plasma α-synuclein can be hypothesized to be the misfolded or fibril conformation α-synuclein; however, the increase in plasma levels associated improved cognitive skills of these children as documented by improved behaviour and communication [5] makes us presume that the circulating plasma α-synuclein can also be the other conformations without misfolding.

The same study revealed the beneficial control of gut enterobacteria [8] in the BRMG group. Enterobacteria are known to secrete curli protein and amyloids, which consist primarily of the misfolded fibril conformation of α-synuclein. Therefore, it is logical to state that it is this misfolded α-synuclein which aggregates in the enteric nervous system not the other normal or beneficial forms of α-synuclein. During the period of consumption of BRMGs, the concentration of misfolded α-synuclein amyloids could have become significantly lower in the enteric nervous system, and the NK cells activated by β-glucans may have cleared the already aggregated misfolded α-synuclein by movement into the circulation and/or appropriate scavenging. Improved communication levels may have possibly increased the synaptic/presynaptic release of normal α-synuclein, which may explain the elevated plasma levels in that study [5].

To address these speculations, a qualitative evaluation of the conformations of plasma and salivary α-synuclein, whether they are normal or misfolded, and the relevant proportions if both types are present, can be accomplished by a clinical study of three groups: (1) children with ASD without intervention such as BRMGs, (2) normal age-matched controls without any intervention, and (3) children with ASD with an intervention of BRMGs. This critical analysis will clarify the pathophysiology of ASD and could be used to plan appropriate remedial and prophylactic measures in the long term.

Author Samuel Abraham is a shareholder in GN Corporation, Japan, which holds shares of Sophy Inc., Japan, the manufacturers of novel beta glucans using different strains of Aureobasidium pullulans; a board member in both the companies; and an applicant to several patents of relevance to these beta glucans.

No external funding was received for this letter.

Kadalraja Raghavan and Samuel J.K. Abraham contributed to conception and design of this letter; Samuel J.K. Abraham and Senthilkumar Preethy drafted the letter; and Nobunao Ikewaki performed critical revision. All the authors read and approved the final version.

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