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The serine-protease OMI/HTRA2, required for several cellular processes, including mitochondrial function, autophagy, chaperone activity, and apoptosis, has been implicated in the pathogenesis of both Alzheimer's disease (AD) and Parkinson's disease (PD). Western blot quantification of OMI/HTRA2 in frontal cortex of patients with AD (n10) and control subjects (n10) in two separate materials indicated reduced processed (active, 35 kDa) OMI/HTRA2 levels, whereas unprocessed (50 kDa) enzyme levels were not significantly different between the groups. Interestingly, the specific protease activity of OMI/HTRA2 was found to be significantly increased in patients with AD (n10) compared to matched control subjects (n10) in frontal cortex in two separate materials. Comparison of OMI/HTRA2 mRNA levels in frontal cortex and hippocampus, two brain areas particularly affected by AD, indicated similar levels in patients with AD (n10) and matched control subjects (n10). In addition, we analyzed the occurrence of the OMI/HTRA2 variants A141S and G399S in Swedish case-control materials for AD and PD and found a weak association of A141S with AD, but not with PD. In conclusion, our genetic, histological, and biochemical findings give further support to an involvement of OMI/HTRA2 in the pathology of AD; however, further studies are needed to clarify the role of this gene in neurodegeneration. [ABSTRACT FROM AUTHOR]

Genes important for mitochondrial function have been implicated in Parkinson's disease (PD). Mitochondrial translation initiation factor 3 (MTIF3) is a nuclear encoded protein required for the initiation of complex formation on mitochondrial ribosomes. Dysfunction of MTIF3 may impairmitochondrial function and dopamine neurons appear to be particularly vulnerable to oxidative stress, which may relate to their degeneration in PD. An association was recently reported between the synonymous rs7669(C>T) in MTIF3 and PD in a German case-control material. We investigated rs7669 in a Swedish Parkinson case-control material. The study revealed no significant association of the individual genotypes or alleles with PD. When comparing the combined TT/CT-genotypes versus the CC-genotype, we observed a significant association (P = .0473) with PD. We also demonstrated that the TT-genotype causes a significant decrease in MTIF3 mRNA expression compared to the CC-genotype (P = .0163). Our findings support the hypothesis that MTIF3 may be involved in the etiology of PD. [ABSTRACT FROM AUTHOR]

The membrane transporter multi-drug resistance 1 (MDR1, P-gp) regulates the bioavailability of endogenous and exogenous compounds and has been implicated in disorders such as Parkinson’s disease, cancer, epilepsy, human immunodeficiency virus disease, and inflammatory bowel disease. To promote further understanding of the role of MDR1 in disease, we have characterized cellular MDR1 mRNA expression in post-mortem human and fresh-frozen Sprague-Dawley rat tissues by using radioactive oligonucleotide probe in situ hybridization. We report MDR1 mRNA in human and rat endothelial cells of small vessels in the brain and pia mater. Mdr1 mRNA is also expressed in the blood vessel walls of rat sensory dorsal root and sympathetic ganglia. In peripheral tissues, we have observed MDR1 mRNA in human and rat liver and renal tubules and in human adrenal cortex and the epithelial lining of rat intestine. In female and male reproductive tissues of rat, strong gene activity has been found in steroid-hormone-synthesizing cells. Quantification of MDR1 mRNA in human striatum has revealed reduced levels in Parkinson patients compared with control individuals. The high expression of MDR1 mRNA in blood vessels of the nervous system, in tissues involved in absorption and excretion, and in tissues forming barriers to the environment support the physiological role of MDR1 as a regulator of intracellular levels of endogenous and exogenous compounds. [ABSTRACT FROM AUTHOR]

Abstract: LRRK2, α-synuclein, UCH-L1 and DJ-1 are implicated in the etiology of Parkinson''s disease. We show for the first time that increase in striatal α-synuclein levels induce increased Lrrk2 mRNA levels while Dj-1 and Uch-L1 are unchanged. We also demonstrate that a mouse strain lacking the dopamine signaling molecule DARPP-32 has significantly reduced levels of both Lrrk2 and α-synuclein, while mice carrying a disabling mutation of the DARPP-32 phosphorylation site T34A or lack α-synuclein do not show any changes. To test if striatal dopamine depletion influences Lrrk2 or α-synuclein expression, we used the neurotoxin 6-hydroxydopamine in rats and MitoPark mice in which there is progressive degeneration of dopamine neurons. Because striatal Lrrk2 and α-synuclein levels were not changed by dopamine depletion, we conclude that Lrrk2 and α-synuclein mRNA levels are possibly co-regulated, but they are not influenced by striatal dopamine levels. [Copyright &y& Elsevier]

Abstract: DJ-1 (PARK7) has been implicated in early onset and familial cases of Parkinson''s disease (PD). We therefore mapped cellular activity patterns of the DJ-1 gene in human and rodent brain tissue with radioactive in-situ hybridization. In all three mammals mRNA expression was restricted mainly to neurons in all regions analyzed. White matter, such as crus cerebri and capsula interna appeared negative, suggesting that glial cells express DJ-1 at levels below the detection limit of our method. We compared DJ-1 mRNA expression to the neuronal marker UCH-L1, which has also been implicated in PD, and found lower levels for DJ-1 but very similar patterns of expression. Measurement of the signal intensity revealed that human frontal cortex of control cases expressed DJ-1 mRNA more abundantly than other regions such as substantia nigra in the midbrain. Comparing DJ-1 expression in dopamine neurons on hemi-sections from controls and patients we could not detect any difference between 14 controls, 8 idiopathic Parkinson and 5 schizophrenia cases. Of note, DJ-1 is expressed in several other tissues such as the liver, gastrointestinal tract, adrenal and pituitary gland and during embryonic development, while UCH-L1 has a strictly neuronal expression also outside the CNS. We conclude that DJ-1 and UCH-L1, like other genes linked to PD, are not expressed specifically in DA neurons, but instead generally in neurons. The abundant expression of DJ-1 in certain peripheral tissues and of UCH-L1 in peripheral neurons may also be of relevance for the spectrum of symptoms in different forms of PD. [Copyright &y& Elsevier]

Parkinson's disease (PD) is a heterogeneous movement disorder characterized by progressive degeneration of dopamine neurons in substantia nigra. We have previously presented genetic evidence for the possible involvement of alcohol and aldehyde dehydrogenases (ADH; ALDH) by identifying genetic variants in ADH1C and ADH4 that associate with PD. The absence of the corresponding mRNA species in the brain led us to the hypothesis that one cause of PD could be defects in the defense systems against toxic aldehydes in the gastrointestinal tract. We investigated cellular expression of Adh1, Adh3, Adh4 and Aldh1 mRNA along the rodent GI tract. Using oligonucleotide in situ hybridization probes, we were able to resolve the specific distribution patterns of closely related members of the ADH family. In both mice and rats, Adh4 is transcribed in the epithelium of tongue, esophagus and stomach, whereas Adh1 was active from stomach to rectum in mice, and in duodenum, colon and rectum in rats. Adh1 and Adh4 mRNAs were present in the mouse gastric mucosa in nonoverlapping patterns, with Adh1 in the gastric glands and Adh4 in the gastric pits. Aldh1 was found in epithelial cells from tongue to jejunum in rats and from esophagus to colon in mice. Adh3 hybridization revealed low mRNA levels in all tissues investigated. The distribution and known physiological functions of the investigated ADHs and Aldh1 are compatible with a role in a defense system, protecting against alcohols, aldehydes and formaldehydes as well as being involved in retinoid metabolism. [ABSTRACT FROM AUTHOR]