Protein tyrosine phosphatases (PTPs) are central players in many different cellular processes and their aberrant activity is associated with multiple human pathologies. In this review, we present current knowledge on the PTPRR subfamily of classical PTPs that is expressed in neuronal cells and comprises receptor-type (PTPBR7, PTP-SL) as well as cytosolic (PTPPBSgamma-37, PTPPBSgamma-42) isoforms. The two receptor-type isoforms PTPBR7 and PTP-SL both localize in late endosomes and the Golgi area. PTPBR7, however, is additionally localized at the cell surface and on early endosomes. During cerebellar maturation, PTPBR7 expression in developing Purkinje cells ceases and is replaced by PTP-SL expression in the mature Purkinje cells. All PTPRR isoforms contain a kinase interacting motif that makes them mitogen-activated protein kinase phosphatases. The distinct subcellular localization of the different PTPRR isoforms may reflect differential roles in growth-factor-induced MAPK-mediated retrograde signaling cascades. Studies in PTPRR-deficient mice established that PTPRR isoforms are physiological regulators of MAPK phosphorylation levels. Surprisingly, PTPRR-deficient mice display defects in motor coordination and balancing skills, while cerebellar morphological abnormalities, which are often encountered in ataxic mouse models, are absent. This is reminiscent of the phenotype observed in a handful of mouse mutants that have alterations in cerebellar calcium ion homeostasis. Elucidation of the molecular mechanisms by which PTPRR deficiency imposes impairment of cerebellar neurons and motor coordination may provide candidate molecules for hereditary cerebellar ataxias that still await identification of the corresponding disease genes.
Cerebrospinal fluid (CSF) levels of amyloid β42 protein (Aβ42), total tau (t–tau) and phosphorylated tau (p–tau) have been extensively studied as biomarkers for dementia syndromes, in particular Alzheimer's disease (AD). In AD, CSF levels of Aβ42, t–tau and p–tau181 are clearly abnormal and may differentiate AD from vascular dementia. However, to distinguish (late–onset) AD from dementia with Lewy bodies (DLB) and (early–onset) AD from frontotemporal dementia (FTD) still remains a challenge, since the specificity of CSF biomarkers is generally low (< 85 percent). We investigated the potential values of CSF neurofilament protein analysis to distinguish AD from FTD and DLB. The study included 70 patients with AD, subdivided in to 37 patients with early–onset AD (EAD, onset before or at 65 years of age, mean age 61.2 ± 4.5 yrs), and 33 patients with late–onset AD (LAD, onset after 65 years of age, mean age 75.6 ± 4.2 yrs). Furthermore, 18 patients with DLB (mean age 72.3 ± 8.5 yrs) and 28 patients with FTD (mean age 63.2 ± 9.1 yrs) were included. A control group without a neurological disorder was included, consisting of twenty–six subjects over age 50 years (mean age 60.9 ± 7.2 yrs). Determination of NF light chain (NFL) and phosphorylated heavy chain (pNFH) levels in CSF was performed using home–made sandwich ELISAs. CSF levels of NFL were significantly higher in FTD patients (mean 20.6 pg/ml) compared to control subjects (6.6 pg/ml; p<0.001) and AD patients (12.3 pg/ml; p<0.05), especially compared to EAD patients (8.5 pg/ml; p<0.01). However, sensitivity (82.1%) and specificity (70.3%) were moderate for the discrimination between FTD and EAD. CSF levels of NFL in DLB patients and LAD patients were comparable. CSF levels of pNFH were significantly elevated in LAD (157 pg/ml; p<0.05), FTD (142 pg/ml; p<0.05), and DLB (182 pg/ml; p<0.001) compared to controls (79 pg/ml). However, no differences in CSF pNFH were found between DLB and LAD patients, or between FTD and EAD patients. CSF NFL levels are elevated in FTD compared to EAD, but its application as a potential biomarker awaits confirmation in a larger patient population.
Amyloid β40 (Aβ40) is the most abundant Aβ peptide in the brain and the cerebrospinal fluid (CSF) level of Aβ40 might therefore be considered to most closely reflect the total Aβ load in the brain. Both in Alzheimer's disease (AD) and in normal aging the Aβ load in the brain has a large inter-individual variability. Relating Aβ42 to Aβ40 levels might consequently provide a biologically more valid measure for reflecting the change in Aβ metabolism in dementia patients than the CSF Aβ42 concentrations alone. In addition, this measure may also improve differential diagnosis between AD and other dementia syndromes, such as frontotemporal dementia (FTD), vascular dementia (VaD) and dementia with Lewy bodies (DLB). We analysed CSF Aβ40, Aβ42, and the Aβ42/Aβ40 ratio in 69 patients with AD, 27 patients with FTD, 26 patients with VaD, 16 patients with DLB, and 47 controls. Mean Aβ40 levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB, both significantly lower than 3698 pg/ml in AD (p<0.01). The Aβ42/Aβ40 ratio was significantly lower in AD patients than in all other groups (p <0.001). Differentiating AD from VaD, DLB and non-AD improved when the Aβ42/Aβ40 ratio was used instead of Aβ42 concentrations alone (p≤0.005). In clinically diagnosed patients with dementia the CSF Aβ42/Aβ40 ratio improves differentiation of AD patients from VaD, DLB and non-AD patients, when compared to Aβ42 alone.
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