Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases

Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.

     

Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration： implications for the pathogenesis of Parkinson＇s disease

While the cause of dopaminergic neuronal cell death in Parkinson＇s disease（PD）is not yet understood,many endogenous molecules have been implicated in its pathogenesis.β-phenethylamine（β-PEA）,a component of various food items including chocolate and wine,is an endogenous molecule produced from phenylalanine in the brain.It has been reported recently that long-term administration ofβ-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins.The toxicity ofβ-PEA has been linked to the production of hydroxyl radical（.OH）and the generation of oxidative stress in dopaminergic areas of the brain,and this may be mediated by inhibition of mitochondrial complex-I.Another significant observation is that administration ofβ-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents.However,no reports are available on the extent of dopaminergic neuronal cell death after administration ofβ-PEA.Based on the literature,we set out to establishβ-PEA as an endogenous molecule that potentially contributes to the progressive development of PD.The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption ofβ-PEA-containing foods is proposed here.Thus,long-term over-consumption of food items containingβ-PEA could be a neurological risk factor having significant pathological consequences.     

Concomitant dysregulation of androgen secretion and dysfunction of adipose tissue induced insulin resistance

Hyperandrogenism and hyperinsulinemia have resulted from dysfunction of the theca cell of the ovary and adipose tissue and each one potentiates the other in patients with androgen excess disorders e.g., polycystic ovary disease and idiopathic hirsutism. Possible external and/or internal triggers can produce such cellular dysfunction. There is evidence that sodium valproate acts as a trigger of cellular dysfunction and produces both hyperinsulinemia and hyperandrogenism. Therefore, the elimination of these triggers can help the patients to recover from hyperinsulinemia, insulin resistance and hyperandrogenism.     

Laccase production by the white-rot fungus Termitomyces clypeatus

Laccase was detected in the culture filtrate of white-rot fungus Termitomyces clypeatus. The enzyme was found at the late phase of submerged growth in a medium containing glucose or cellulose as the carbon source. The present study indicates that laccase produced by T. clypeatus is an intracellular enzyme, released in the medium due to cell lysis at the end of the growing phase. Laccase produced by T. clypeatus is different from the extracellular polyphenol oxidase of T. albuminosus, also produced at the late phase of growth. This is the first report of laccase production by a Termitomyces sp.