No abstract

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signaling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau, and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T > G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C > A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA ortholog knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

BackgroundBackground: CAG-repeat expansions in Ataxin 2 (ATXN2) are known to cause spinocerebellar ataxia type 2 (SCA2), but CAA interrupted expansions may also result in autosomal dominant Parkinson's disease (AD PD). However, because of technical limitations, such expansions are not explored in whole exome sequencing (WES) data. Objectives Objectives: To identify ATXN2 expansions using WES data from PD cases. Methods Methods: We explored WES data from a cohort of 477 index cases with PD using ExpansionHunter (Illumina DRAGEN Bio-IT Platform, San Diego, CA). Putative expansions were confirmed by combining polymerase chain reaction and fragment length analysis followed by sub-cloning and sequencing methods. ResultsResults: Using ExpansionHunter, we identified three patients from two families with AD PD carrying either ATXN2 22/39 or 22/37 repeats, both interrupted by four CAA repeats. Conclusion Conclusion:These findings demonstrate the usefulness of WES to detect pathogenic CAG repeat expansions, which were found in 1.7% of AD PD in the ATXN2 gene in our exome dataset.Parkinson's disease (PD) is a neurodegenerative disorder characterized by a triad of symptoms: akinesia, rigidity, and rest tremor, and is associated with a good response to levodopa therapy. These symptoms are because of the degeneration of dopaminergic neurons of the substantia nigra secondary to the accumulation of aggregated α-synuclein. [1][2][3] Although the cause of PD is commonly sporadic, Mendelian forms account for 5% to 10% of cases. 4 Disease causing variants, mostly in SNCA, LRRK2, and VPS35 have been identified in patients with autosomal dominant (AD) PD. In addition, we and others have previously described families with heterozygous expansions in Ataxin 2 (ATXN2) presenting with predominant parkinsonian symptoms and in some cases with typical AD PD. [5][6][7][8][9][10][11] As in ataxic forms of spinocerebellar ataxia type 2 (SCA2), the expanded allele contained >33 repeats, but in PD, they were often interrupted by one or more CAA codons. 12 Next-generation sequencing (NGS) has proven to be of great diagnostic value in clinical practice, 13 but until recently, was thought to have a limited ability to assess for loci containing repeat expansions. Over the last few years, several bioinformatic tools for genome-wide genotyping of short tandem repeats (STRs) in short read sequencing data, mainly from whole genome sequencing (WGS) data have been developed. [14][15][16][17] However, despite the extensive application of whole exome