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C Warren Olanow

Publications and source records attributed to C Warren Olanow.

58 records · Page 4Linked to original sources
PubMed2002

Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures.

Mutations in alpha-synuclein, parkin and ubiquitin C-terminal hydrolase L1, and defects in 26/20S proteasomes, cause or are associated with the development of familial and sporadic Parkinson's disease (PD). This suggests that failure of the ubiquitin-proteasome system (UPS) to degrade abnormal proteins may underlie nigral degeneration and Lewy body formation that occur in PD. To explore this concept, we studied the effects of lactacystin-mediated inhibition of 26/20S proteasomal function and ubiquitin aldehyde (UbA)-induced impairment of ubiquitin C-terminal hydrolase (UCH) activity in fetal rat ventral mesencephalic cultures. We demonstrate that both lactacystin and UbA caused concentration-dependent and preferential degeneration of dopaminergic neurons. Inhibition of 26/20S proteasomal function was accompanied by the accumulation of alpha-synuclein and ubiquitin, and the formation of inclusions that were immunoreactive for these proteins, in the cytoplasm of VM neurons. Inhibition of UCH was associated with a loss of ubiquitin immunoreactivity in the cytoplasm of VM neurons, but there was a marked and localized increase in alpha-synuclein staining which may represent the formation of inclusions bodies in VM neurons. These findings provide direct evidence that impaired protein clearance can induce dopaminergic cell death and the formation of proteinaceous inclusion bodies in VM neurons. This study supports the concept that defects in the UPS may underlie nigral pathology in familial and sporadic forms of PD.

Acetylcysteine↗
PubMed2002

Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson's disease.

Motor complications are a major source of disability for patients with advanced Parkinson's disease. Surgical therapies provide benefit to some, but these treatments are expensive and associated with adverse effects. Current research indicates that motor complications are associated with abnormal, intermittent, pulsatile stimulation of denervated dopamine receptors using short acting dopaminergic agents such as levodopa. Retrospective studies suggest that the use of longer-acting more continuous dopaminergic therapies can improve both motor fluctuations and dyskinesia. We performed a prospective, long-term (4-year) trial comparing patients randomized to receive subcutaneous infusion of the dopamine agonist lisuride versus conventional therapy with oral levodopa and dopamine agonists. We demonstrate that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesia compared with patients receiving standard dopaminergic therapies. Benefits persisted for the 4-year duration of the study. Mean Unified Parkinson's Disease Rating Scale scores in "ON" and "OFF" states did not significantly change between baseline and 4 years for patients in the lisuride group, but deteriorated in patients in the levodopa group. This study indicates that continuous lisuride infusion can be beneficial for patients with advanced Parkinson's disease and reverse established motor fluctuations and dyskinesia.

Administration, Oral↗
PubMed2001

Distribution and immunohistochemical characterization of torsinA immunoreactivity in rat brain.

A mutation of the DYT1 gene on chromosome 9q34 has recently been identified as the cause of one form of autosomal-dominantly inherited dystonia. TorsinA, the protein product of this gene, has homology with the family of heat shock proteins, and is found in many peripheral tissues and brain regions. We used a polyclonal antibody to torsinA, developed in our laboratory, to systematically examine the regional distribution of torsinA in rat brain. We find that neurons in all examined structures are immunoreactive for this protein. There is intense immunoreactivity in most neuronal nuclei, with slightly less labeling of cytoplasm and proximal processes. Terminals also are labeled, especially in striatum, neocortex and hippocampus. Double-labeling fluorescence immunohistochemistry using antibodies to neurotransmitters and other neurochemical markers demonstrated that the majority of neurons of all studied neurochemical types are immunoreactive for torsinA. Our findings indicate that torsinA is widely distributed in the central nervous system implicating additional, localized factors, perhaps within the basal ganglia, in the development of dystonia. Many other proteins have a similar widespread distribution, including some which have been implicated in other movement disorders and neurodegenerative processes, such as parkin, alpha-synuclein, ubiquitin and huntingtin. The distribution of torsinA in rat brain as demonstrated by immunohistochemistry contrasts with the results of in situ hybridization studies of torsinA mRNA in human postmortem brain in which a more limited distribution was found.

Animals↗