The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders

Abstract

Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.

Yield of array‐CGH analysis in Tunisian children with autism spectrum disorder

“…Most other “pathogenic” and “likely pathogenic” CNVs do not overlap nor appear similar to CNVs listed in Decipher, but they do span “autism genes” listed in the SFARI GENE , and AutismKB databases, such as DMD, NEXMIF, NLGN4X, PRKN , and others (Table 2 ). Their role in ASD and in other neurodevelopmental disorders has been reported in several studies (Aradhya et al, 2007 ; Bourgeron, 2015 ; Morato Torres et al, 2020 ; Satterstrom et al, 2020 ; Yuen et al, 2017 ). Patient n. 42 is a 5‐year‐old boy who carries an Xp21.2 duplication involving exons 61–79 of the full‐length isoform and the entire shortest isoform of the dystrophin ( DMD ) gene.…”

Neuropathological Findings in a Case of Parkinsonism and Developmental Delay Associated with a Monoallelic Variant in PLXNA1

“…For example, copy number variants associated with the PRKN gene and mutations in SNCA (α-synuclein) have been implicated in the development of both autism spectrum disorder (ASD) and PD. 8 Plasma α-synuclein and gamma-synuclein with severity of ASD have also been correlated. 9 In this report we discuss the clinical features and post-mortem neuropathologic findings of an individual with intellectual disability, congenital eye anomalies, seizures, and early-onset parkinsonism, with a pathogenic variant in PLXNA1.…”

The Association between α-Synuclein and α-Tubulin in Brain Synapses

“…On these bases, our findings could suggest new investigations on the α-synuclein/α-tubulin interplay, not only in classical synucleinopathies but also in other neuropathologies such as Alzheimer's disease and epilepsy where synaptic dysfunction frequently underlies the respective clinical pictures [57]. Interestingly, studies on neurodevelopmental diseases point out the role of both deletion or partial duplication of the α-synuclein gene [67] and genetic mutations in microtubule-associated genes or defective regulation of microtubules in the pathophysiology of autism spectrum disorder [68]. This could permit speculation on the existence of a converging mechanism that involves both α-synuclein and tubulin cytoskeleton in neurodegenerative as well as neurodevelopmental disorders.…”