Interplay between PFBC-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis

Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters in the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis and identify XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of wildtype SLC20A2 increases phosphate uptake as expected, but also unexpectedly increases phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1-KO cells. Elevated ATP is a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with wildtype XPR1, but not with XPR1 harboring a mutated PP-IP-binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (IP6K1-2) gene inactivation or IP6K inhibitor treatment abolished XPR1-mediated phosphate efflux regulation and homeostasis. Our findings unveil an SLC20A2-XPR1 interplay that depends on IPs such as PP-IPs and controls cellular phosphate homeostasis via the efflux route, and that alteration of this interplay likely contributes to PFBC

Diffuse neurofibrillary tangles with calcification: A single entity or two disorders in a single patient?

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Atypical inflammatory demyelinating lesions and atypical multiple sclerosis

International audienceAtypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló's concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management

Glatiramer acetate-induced hepatitis in a patient with multiple sclerosis

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CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy: mystery case responses

A 37-year-old man was referred for a 1-year history of word naming difficulties and progressive executive dysfunction along with anxiety. Clinical examination showed generalized hyperreflexia and bilateral Babinski sign but was otherwise normal. His brain MRI (figure, A and B) showed extensive leukoencephalopathy with multiple small cysts within the white matter changes and no gadolinium enhancement. CT identified punctate calcifications with deep frontal and juxtacortical distribution (figure, C and D). His mother died at 63 years after a 10-year history of progressive cognitive impairment of frontal type, walking difficulties, and urinary incontinence. Her brain imaging was strikingly similar to her son's (figure, E–H).</p

Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy: [RETRACTED]

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