Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation.

PTEN-induced putative kinase 1 (PINK1) is an integral protein in the mitochondrial membrane and maintains mitochondrial fidelity. Pathogenic mutations in PINK1 have been identified as a cause of early-onset autosomal recessive familial Parkinson's disease (PD). The ubiquitin proteasome pathway is associated with neurodegenerative diseases.

Increase of oxidative stress by a novel PINK1 mutation, P209A.

Mutation in the human PTEN-induced protein kinase 1 (PINK1) gene is responsible for the second most common form of recessive Parkinson disease (PD). We have identified a single heterozygous PINK1 mutation, P209A, from a cohort of 68 patients with early onset PD. From age 31, this patient developed an asymmetric bradykinesia with rigidity that was L-DOPA responsive.

Acetazolamide impairs fear memory consolidation in rodents.

Acetazolamide (AZ) is an carbonic anhydrase inhibitor, which has been used in the treatment of seizures, mountain sickness and glaucoma. Memory impairment by AZ has been reported in patient interviews; however, the related mechanism is unclear. We applied two fear conditioning paradigms, shuttle avoidance and passive avoidance, in both rats and mice to investigate this clinical anecdote.

Impairment of oxidative stress-induced heme oxygenase-1 expression by the defect of Parkinson-related gene of PINK1.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Mutation in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene causes an autosomal recessive form of PD. However, the etiology related to PINK1 is still not clear.

Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.

TDP-43 is a multifunctional DNA/RNA-binding factor that has been implicated in the regulation of neuronal plasticity. TDP-43 has also been identified as the major constituent of the neuronal cytoplasmic inclusions (NCIs) that are characteristic of a range of neurodegenerative diseases, including the frontotemporal lobar degeneration with ubiquitin(+) inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). We have generated a FTLD-U mouse model (CaMKII-TDP-43 Tg) in which TDP-43 is transgenically overexpressed in the forebrain resulting in phenotypic characteristics mimicking those of FTLD-U.

Enhancement of active shuttle avoidance response by the NO-cGMP-PKG activator YC-1.

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about the signaling pathway involved in the acquisition of an active avoidance reaction. The aim of this study is to investigate the potentiating effects of the NO-guanylate cyclase activator YC-1 on learning and memory of shuttle avoidance test in rats. YC-1 enhanced the induction of long-term potentiation (LTP) in amygdala through NO-cGMP-PKG-ERK pathway and the increase of BDNF expression.

Mice deficient in collapsin response mediator protein-1 exhibit impaired long-term potentiation and impaired spatial learning and memory.

Collapsing response mediator protein-1 (CRMP-1) was initially identified in brain and has been implicated in plexin-dependent neuronal function. The high amino acid sequence identity among the five CRMPs has hindered determination of the functions of each individual CRMP. We generated viable and fertile CRMP-1 knock-out (CRMP-1(-/-)) mice with no evidence of gross abnormality in the major organs.

Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1.

Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC-1, which is a benzylindazole derivative, greatly potentiated the response of soluble guanylate cyclase to NO (up to several hundreds fold).

Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole.

Nitric oxide (NO) is known to affect synaptic plasticity in various regions of the brain via the cGMP-cGMP-dependent protein kinase (PKG) pathway. We found that a novel compound 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole (YC-1), a drug known to modulate the response of soluble guanylyl cyclase to NO, greatly potentiates long-term potentiation (LTP). This compound markedly enhanced the induction of LTP in rat hippocampal and amygdala slices by weak tetanic stimulation.