Study Group † Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations.

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.

Background: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder associated with cognitive decline and is the most common form of dementia in the elderly. Early-onset familial AD accounts for less than 1% of AD cases and develops before the age of 65 years because of mutations in either the APP gene or genes encoding presenilin 1 (PSEN1) or presenilin 2 (PSEN2). The majority of sporadic AD cases are referred to as late-onset AD (LOAD) because they occur late in life (>65 years). Apolipoprotein E (APOE) polymorphic alleles are the major genetic risk factor for AD. The human APOE gene exists as three polymorphic alleles, ε2, ε3, and ε4, with a worldwide frequency of 8%, 78%, and 13%, respectively, with ε4 reaching frequencies of 40% in AD patients. The purpose of this preliminary study was to determine ApoE genotype status since no previous association studies between LOAD and ApoE gene were available for the Central Algerian population. Methods: The cohort of our study was composed of 47 AD patients recruited from the Neurology Department of Frantz Fanon Hospital of Blida. Forty-seven controls with no type of dementia were also included in the study. All samples were genotyped for the ApoE Polymorphisms by PCR-RFLP method. Statistical studies can use the Fisher exact test or Chi-2 using the GraphPad Prism 7.0 software. Results:The results show that the genotype ɛ3/ɛ3 is most common in both groups followed by the heterozygous genotype ɛ3/ɛ4 which showed an increased frequency in patients compared to controls (27.66% vs. 12.77%, OR=3.66, p=0,11). Although rare, all other possible genotypes have been observed in our cohort, namely ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4 and ɛ4/ɛ4. The ɛ2/ɛ4 genotype was observed only in AD patients, while the ɛ2/ɛ2 genotype was observed only in controls. As expected, the homozygous genotype ɛ4/ɛ4 was more frequent in AD patients, compared to controls (6.38% vs. 2.13%, respectively OR=2.64, IC=0. 36-37.33; p=0,33). At the allelic level, ɛ4 allele was significantly associated with AD compared to controls (21,28% vs. 4,26% ; OR= 2.75, 95% CI= 1.109-6.35; p = 0.02, respectively), while the ɛ2 allele seems to be protective (4,26% vs. 9,57%, OR = 0.49 ; 95% CI=0.14-1.66 ; p=0,38, respectively), but without statistical significance. In population-based studies, the ApoEɛ4-AD association was weaker among African Americans (ε4/ε4, OR 5.7) and Hispanics (ε4/ε4, OR 2.2) and was stronger in the Japanese population (ε4/ε4, OR 33.1) compared with Caucasian cases (ε4/ε4, OR 12.5). The results obtained in our

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