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 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.

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death

“…Notably, the variation that was identified in TRIM41 affects its PRY-SPRY domain [ 131 ]. In addition, SNCA gene deletions and partial duplication have been found in ASD patients [ 135 , 136 ]. As accumulating arguments suggest that α-synuclein may be involved in ASD pathogenesis [ 136 ], it is tempting to speculate that TRIM17 may also play a role in ASD by altering α-synuclein expression through its action on TRIM41 and ZSCAN21.…”

Plasma Levels of Alpha and Gamma Synucleins in Autism Spectrum Disorder: An Indicator of Severity

“…A recent study reported a strong association between neurodegenerative and neurodevelopmental disorders, specifically PD and ASD [11]. This association includes genetic, molecular, and even clinical similarities between these disorders.…”

Dopaminergic neurons in chromosome 22q11.2 deletion syndrome

“…Other symptoms include early dystonia, history of seizures, and neuropsychiatric symptoms [5] . 22q11DS-associated PD has clinical and neuropathological features similar to sporadic PD and some cases of hereditary PD [6] .…”

“…It has recently been recognized that adults with 22q11DS are at an increased risk of developing Parkinson disease (PD) [5] . Clinically, the onset of symptoms is asymmetric and is typically accompanied by progressive bradykinesia, rigidity, and tremor [6] . Typically, patients respond well to levodopa therapy [7] .…”