PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

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.

Cross‐Ethnic Variant Screening and Burden Analysis of PTPA in Parkinson's Disease

“…To further explore the effect of the variant p.-Met329Val on the expression of PTPA, we assessed RNA and protein levels via Western blotting and RT-qPCR by overexpressing wild-type PTPA (PTPA WT ) and p.Met329Val PTPA (PTPA M329V ) as previously reported. 5 We found a significant reduction in protein levels in cells expressing PTPA M329V compared with PTPA WT , while no significant difference in PTPA mRNA expression was observed (Fig. 2A-C).…”

“…Recently, two homozygous variants (p.Met298Arg, p.Ala171Asp) in PTPA ( protein phosphatase 2A ) were identified as the disease cause in two pedigrees of African descent 5 . The patients had early‐onset parkinsonism and intellectual disability.…”

“…2 Recently, two homozygous variants (p.Met298Arg, p.Ala171Asp) in PTPA (protein phosphatase 2A) were identified as the disease cause in two pedigrees of African descent. 5 The patients had early-onset parkinsonism and intellectual disability. The study further demonstrated that PTPA ortholog knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test.…”

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

“…Many Whole Exome Sequencing projects have been recently conducted in large cohorts of patients but have resulted in very few novel PD-causative genes. 27 These observations suggest either the possibility of an incomplete detection of variants in already known PD genes using conventional molecular approaches, or the existence of other still-unknown genetic factors, possibly acting in a multifactorial model to influence PD susceptibility even in patients with early onset of the disease. 28,29 It is expected that large ongoing projects on PD genetics, such as the worldwide GP2 effort (Global Parkinson's Genetic Project; https://gp2.org), will eventually address this major unsolved issue.…”

Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α-Synuclein Mouse Models of Parkinson’s Disease

“…Together, increased ROS production and αSyn aggregation accompanied by impaired autophagy create a vicious cycle that leads to neuronal cell death in Parkinson’s disease (PD). Moreover, decreased PP2A levels and activity have been implicated in the pathophysiology of Alzheimer’s disease and PD, , and a recent study identified point mutations in an endogenous PP2A activator, leading to reduced PP2A activity, proposed to contribute to early onset PD . Therefore, PP2A activating compounds could tackle several pathophysiological mechanisms in neurodegenerative diseases and eventually lead to a disease-modifying effect.…”