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

• Published in: International journal of molecular sciences Vol. 21; no. 16; p. 5724
• Main Authors: Morato Torres, C Alejandra, Wassouf, Zinah, Zafar, Faria, Sastre, Danuta, Outeiro, Tiago Fleming, Schüle, Birgitt
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.08.2020; MDPI
• Subjects: 22q11.2 deletion syndrome; Adolescent; Adult; Age; Aged; Aged, 80 and over; alpha-synuclein; alpha-Synuclein - blood; alpha-Synuclein - genetics; Animals; Anxiety; Autism; Autism Spectrum Disorder - blood; Autism Spectrum Disorder - genetics; autism spectrum disorders; Behavior; Child; Child, Preschool; Chromosome 22; Chromosome deletion; Chromosomes; Convergence; Dementia; DiGeorge Syndrome - genetics; Disease; Disease Models, Animal; Dopamine; Female; Females; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Gene Dosage; Genes; Genomes; Humans; Infant; Infant, Newborn; Intellectual disabilities; Male; Males; Mice; Middle Aged; Molecular modelling; Mutation; Neurodegeneration; Neurodevelopmental disorders; Neurogenesis; Neurogenesis - genetics; PARK2; Parkin protein; Parkinson Disease - blood; Parkinson Disease - genetics; Parkinson's disease; Pathophysiology; Patients; Phenomenology; Phenotypes; Point Mutation; Proteins; Review; Risk analysis; Risk factors; SNCA; Social interaction; Studies; Synapses - metabolism; Synapses - pathology; Synuclein; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; 22q11.2 deletion syndrome; neuronal development; neurodegeneration; autism spectrum disorders; synaptic dysfunction; alpha-synuclein; PARK2; Parkinson’s disease; SNCA
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21165724

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 (alpha-synuclein), (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and (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.