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


Morato Torres CA, Wassouf Z, Zafar F, Sastre D, Outeiro TF, Schüle B


International Journal of Molecular Sciences


Int. J. Mol. Sci. 2020, 21(16), 5724.


Neurodevelopmental and late-onset neurodegenerative disorders present as separateentities that are clinically and neuropathologically quite distinct. However, recent evidence hashighlighted surprising commonalities and converging features at the clinical, genomic, and molecularlevel between these two disease spectra. This is particularly striking in the context of autismspectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a centralrole in disease pathophysiology and enable the identification of overlapping mechanisms andpathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical andcellular features of ASD and PD. Several genes and genomic regions were selected for our review,includingSNCA(alpha-synuclein),PARK2(parkin RBR E3 ubiquitin protein ligase), chromosome 22q11deletion/DiGeorge region, andFMR1(fragile X mental retardation 1) repeat expansion, which influencethe development of both ASD and PD, with converging features related to synaptic function andneurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representingearly and key disease phenotypes, which support the hypothesis of converging mechanisms betweenthe two types of diseases. Therefore, understanding the underlying molecular mechanisms mightinform on common targets and therapeutic approaches. We propose to re-conceptualize howwe understand these disorders and provide a new angle into disease targets and mechanisms linkingneurodevelopmental disorders and neurodegeneration.



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