Wolframin is a novel regulator of tau pathology and neurodegeneration.

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.

Clozapine modulates aromatic L-amino acid decarboxylase activity in mouse striatum.

Clozapine is efficacious for treating dopaminergic psychosis in Parkinson's disease and ameliorates l-DOPA-induced motor complications. Based on its pharmacology and reported enhancing effects on dopamine metabolism and tyrosine hydroxylase activity, we investigated whether it could modulate the activity of aromatic l-amino acid decarboxylase (AAAD), the second enzyme for the biosynthesis of catecholamines and indoleamines. A single dose of clozapine increased AAAD activity of striatum in a dose- and time-dependent manner. At 1 h, enhanced enzyme activity was characterized by an increased V(max) for substrate and cofactor and was accompanied by elevated levels of protein in striatum and mRNA in substantia nigra, ventral tegmental area, locus coeruleus, and raphe nuclei. Acute clozapine increased tyrosine hydroxylase activity in striatum but with differing temporal patterns from AAAD and heightened dopamine metabolism. Interestingly, the response of the dopaminergic markers to clozapine was greater following a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. Chronically administered clozapine increased AAAD activity and protein and dopamine metabolism in striatum without affecting tyrosine hydroxylase. Exogenous l-DOPA decarboxylation was accelerated in the striatum of intact and MPTP-lesioned mice following acute clozapine, and the effect was exaggerated in the MPTP mice. To identify receptors involved, antagonists of receptors occupied by clozapine were employed. D4, 5-HT1(A), and 5-HT2(A), in addition to D1, D2, and D3, antagonists, augmented AAAD activity in striatum, whereas 5-HT2(C), 5-HT3, muscarinic, and alpha-1 and alpha-2 adrenergic antagonists were ineffective. For the first time, these studies provide evidence that clozapine modulates AAAD activity in the brain and suggests that dopamine and serotonin receptors are involved.