myelin-basic-protein and Neuronal-Ceroid-Lipofuscinoses

Topics: Alzheimer Disease; Aminopeptidases; Animals; Apolipoproteins E; Blood-Brain Barrier; Blood-Retinal Barrier; Chloroplasts; Cholera Toxin; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Female; Humans; Male; Myelin Basic Protein; Neuronal Ceroid-Lipofuscinoses; Peptides; Plaque, Amyloid; Serine Proteases; Tripeptidyl-Peptidase 1

Anomalies in neuropeptides and neuroactive amino acids have been postulated to play a role in neurodegeneration in a variety of diseases including the inherited neuronal ceroid lipofuscinoses (NCLs, Batten disease). These are often indicated by concentration changes in cerebrospinal fluid (CSF). Here we compare CSF neuropeptide concentrations in patients with the classical juvenile CLN3 form of NCL and the classical late infantile CLN2 form with neuropeptide and neuroactive amino acid concentrations in CSF from sheep with the late infantile variant CLN6 form. A marked disease related increase in CSF concentrations of neuron specific enolase and tau protein was noted in the juvenile CLN3 patients but this was not observed in an advanced CLN2 patient nor CLN6 affected sheep. No changes were noted in S-100b, GFAP or MBP in patients or of S-100b, GFAP or IGF-1 in affected sheep. There were no disease related changes in CSF concentrations of the neuroactive amino acids, aspartate, glutamate, serine, glutamine, glycine, taurine and GABA in these sheep. The changes observed in the CLN3 patients may be progressive markers of neurodegeneration, or of underlying metabolic changes perhaps associated with CLN3 specific changes in neuroactive amino acids, as have been postulated. The lack of changes in the CLN2 and CLN6 subjects indicate that these changes are not shared by the CLN2 or CLN6 forms and changes in CSF concentrations of these compounds are unreliable as biomarkers of neurodegeneration in the NCLs in general.

Topics: Age Factors; Amino Acids; Animals; Biomarkers; Child; Child, Preschool; Female; Glial Fibrillary Acidic Protein; Humans; Insulin-Like Growth Factor I; Male; Myelin Basic Protein; Nerve Growth Factors; Neuronal Ceroid-Lipofuscinoses; Neuropeptides; Neurotransmitter Agents; Phosphopyruvate Hydratase; Predictive Value of Tests; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Sheep; tau Proteins; Tripeptidyl-Peptidase 1

Acetyl-L-carnitine (ALC) is a naturally occurring substance that, when administered at supraphysiological concentration, is neuroprotective. It is a molecule of considerable interest for its clinical application in various neural disorders, including Alzheimer's disease and painful neuropathies. Suppression subtractive hybridization methodology was used for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after ALC treatment. The method generates an equalized representation of differentially expressed genes irrespective of their relative abundance and it is based on the construction of forward and reverse cDNA libraries that allow the identification of the genes which are regulated by ALC. We report that ALC treatment: (1) upregulates lysosomal H(+)/ATPase gene expression and (2) downregulates myelin basic protein gene expression. The expression of these genes is altered in some forms of neuronal ceroid lipofuscinosis (NCL) pathologies. In this case, ALC might rebalance the disorders underlying NCL disease represented by a disturbance in pH homeostasis affecting the acidification of vesicles transported to lysosomal compartment for degradation. This study provides evidence that ALC controls genes involved in these serious neurological pathologies and provides insights into the ways in which ALC might exert its therapeutic benefits.

Topics: Acetylcarnitine; Animals; Brain; Gene Expression Regulation; Humans; Male; Myelin Basic Protein; Neuronal Ceroid-Lipofuscinoses; Nootropic Agents; Protein Subunits; Rats; Rats, Wistar; Vacuolar Proton-Translocating ATPases