Nirit Lev

Role of DJ-1 in parkinson’s disease

Parkinsons disease (PD), one of the most common neurodegenerative diseases, is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years, including α-synuclein, parkin, PINK1, dardarm (LRRK2), and DJ-1. DJ-1 deletions and point mutations have been found worldwide, and loss of functional protein was shown to cause autosomal recessive PD. Moreover, DJ-1 immunoreactive inclusions are found in other α-synucleopathies and tauopathies, indicating that different neurodegenerative diseases might share a common mechanism in which DJ-1 might play a key role. The function of DJ-1 is still unknown; however, it is associated with various cellular processes, including response to oxidative stress, cellular transformation, RNA-binding, androgen-receptor signaling, spermatogenesis, and fertilization. This article reviews the current knowledge on DJ-1, focusing on its importance in the pathogenesis of PD.

Regulation of adenylate cyclase type VIII splice variants by acute and chronic Gi/o-coupled receptor activation

We previously reported that acute agonist activation of G(i/o)-coupled receptors inhibits adenylate cyclase (AC) type VIII activity, whereas agonist withdrawal following chronic activation of these receptors induces AC-VIII superactivation. Three splice variants of AC-VIII have been identified, which are called AC-VIII-A, -B and -C (with AC-VIII-B missing the glycosylation domain and AC-VIII-C lacking most of the C1b area). We report here that AC-VIII-A and -B, but not -C, are inhibited by acute mu-opioid and dopaminergic type D2 receptor activation, indicating that the C1b area of AC-VIII has an important role in AC inhibition by G(i/o)-coupled receptor activation. On the other hand the glycosylation sites in AC-VIII did not play a role in AC-VIII regulation. Although AC-VIII-A and -C differed in their capacity to be inhibited by acute agonist exposure, agonist withdrawal after prolonged treatment led to a similar superactivation of all three splice variants, with no significant change in AC-VIII expression. AC-VIII superactivation was not affected by pre-incubation with a cell permeable cAMP analogue, indicating that the superactivation does not depend on the agonist-induced reduction in cAMP levels. The superactivated AC-VIII-A, -B and -C were similarly re-inhibited by re-application of agonist (morphine or quinpirole), returning the activity to control levels. These results demonstrate marked differences in the agonist inhibition of the AC-VIII splice variants before, but not after, superactivation.