Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

Abstract

Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson’s disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis.

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

“…Recent genetic studies have taken the considerable overlap of clinical and pathological features of PD, ALS, and MSA into account, and have highlighted the importance of testing known pathological genetic mutations across these neurodegenerative diseases [ 141 , 142 , 143 ]. Collectively, these studies found no association between PD-related SNCA variants and ALS, however, their analyses focused on SNP-based risk association, and it has been previously shown that only ~8% of heritability in ALS is associated with genome-wide SNPs [ 144 ].…”

Functional characterization of ATP13A2 variants associated with distinct neurodegenerative disorders

“…ALS patients exhibit a higher prevalence of Lewy body disease and 30% of ALS patients present parkinsonian features. PD-causative genes have therefore been proposed as risk modifiers in ALS and a higher frequency of mutations in autosomal recessive PD genes has been reported in the ALS versus control cohort [31]. The genetic link between ATP13A2 and ALS is however not solid, and is mainly based on a report describing a patient carrying a homozygous truncation variant in ATP13A2 (among variants in more than 25 other genes) [4].…”

“…We found that this variant had only a modest impact on spermine uptake in cells (a of approximately 20%), while the ATPase activity in microsomes was not affected, questioning whether this variant may be diseasecausing. Four more variants in ATP13A2 have recently been identified in a cohort of 330 ALS patients, but detailed clinical and allele information is lacking [31]. Of these, the A461Vfs*5 variant is most likely disruptive, but was identified in a patient with disease onset at the age of 87.…”

“…No information is available for the P983S variant, whereas the I946F and Y1020C variants have also been observed in a patient with either PD [32] or MSA [6], respectively. The ALS patient with the Y1020C variant also carried a mutation in SOD1, a known ALS-causative gene [31]. It is clear that additional genetic, clinical, and biochemical evidence will be required before a genetic association of ATP13A2 with ALS can be conclusively established.…”

Current understanding of the association between Amyotrophic lateral sclerosis and frontotemporal dementia: Letter to Editor

“…This overlap in pathological features has led to the recognition of a new pathological entity known as TDP-43 proteinopathy, which is characterized by the accumulation of abnormal TDP-43 protein in the brain and spinal cord. TDP-43 proteinopathy has been identified in both ALS and FTD patients, suggesting that they may share a common underlying pathology (7).…”