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

C Alejandra Morato Torres,Birgitt Schüle,Zinah Wassouf,Danuta Sastre,Faria Zafar,Tiago Fleming Outeiro

doi:10.3390/ijms21165724

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.

Highlights

Introduction of Clinical Aspects ofParkinson’s Disease (PD) and Autism Spectrum Disorders (ASDs)Early onset neurodevelopmental and late-onset neurodegenerative disorders present as entities that appear quite distinct
While in Parkinson’s disease (PD), point mutations and non-coding risk variants have been predominantly described, only Copy number variants (CNVs) alterations have been described in ASD; we describe the frequencies for CNVs in the PARK2 gene and 22q11.2 deletions, and FMR1 protein (FMRP) translational regulator 1 (FMR1) repeat expansions, which can present both with clinical symptoms of PD and ASD
While overexpression of the SNCA gene has been accepted as being causative for PD and related neurodegenerative conditions, we propose that deletions or partial duplications of the SNCA genomic regions lead to developmental delay and ASD and relevant models could shed light on this connection and mechanisms possible linked through synaptic function and neuronal development

Summary

Overlapping Clinical Motor and Behavioral Phenomenology between ASD and PD

Loss of dopaminergic signaling in the nigro-striatal pathway is the primary cause for the motor symptoms in PD, causing an imbalance in the neuronal circuits of basal ganglia. A closer look into public disease databases (e.g., ClinVar, Decipher, and ISCA) and large cohort studies for CNV variation in neurocognitive disorders reveals that there are patients with large deletions of the SNCA locus, which clinically present with developmental delay, ASD, and/or congenital abnormalities. Of note, these cases are distinct from chromosome 4q deletion syndromes, which encompass either a proximal deletion between 4(q11–q31) or distal deletion of 4(q31–q35) [124,125]. Seven patients and two controls carried a 475-kb deletion (NCBI36/hg; chr.4:90,793,560-91,268,616), including only the SNCA and MMRN1 genes [128]

Four PD-Associated Genes Are Linked with Neurodevelopmental Disorders

Double Synuclein KO Models Show Compensatory Increase of β- or γ-Syn

Triple SYN-KO Models Display Smaller Synapses

Key Concepts and Future Directions