Peter Riederer

Selective Insolubility of α-Synuclein in Human Lewy Body Diseases Is Recapitulated in a Transgenic Mouse Model

α-Synuclein (α-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson’s disease (PD) and LB dementias. α-SYN forms LB-like fibrils in vitro, in contrast to its homologue β-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]α-SYN driven by the brain neuron-specific promoter, Thy1. Distinct α-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human α-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse α-SYN nor β-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic β-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of α-SYN are absent in β-SYN. In conclusion, the specific accumulation of detergent-insoluble α-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.

Parkinsonism in HIV dementia.

Summary. A great number of human immunodeficiency virus (HIV)-infected patients develop a central nervous system disorder, commonly called HIV dementia or AIDS dementia complex (ADC). HIV dementia is independent of opportunistic infections and is due to the virus itself. Symptoms include psychomotor slowing, apathy and motor disorders similar tothe bradykinesia and postural and gait abnormalities observed in late Parkinsons disease. Consequently, HIV has been discussed during the last few years as an additional cause for parkinsonism, and parkinsonian syndromes as manifestations of HIV dementia. Moreover, the early phase of HIV infection gains increasing interest because of studies which report subtle neurological symptoms at this stage. Accordingly, we found in SIV-infected monkeys that dopamine is reduced by 44% within as few as two months of infection, indicating that changes during early infection must be thoroughly evaluated. In this short review, we discuss alterations in the nigrostriatal dopaminergic system during early and late immunodeficiency virus infection and the common clinical and biochemical features shared by HIV dementia and Parkinsons disease.

Neurotransmission in HIV associated dementia: a short review.

Summary. Human immunodeficiency virus (HIV) infection is frequently associated with specific neurological and psychiatric symptoms. Our understanding of how HIV-related CNS deficits develop is still preliminary and the cause remains obscure. However, some clues have emerged which may clarify uncertainties. Following a brief discussion of the epidemiology underlying neuropathological mechanisms and clinical symptoms in HIV-infected patients, we focus our attention on neurochemical data obtained by studies in humans and rhesus monkeys which provide information on the effect of the retroviral infection on neurotransmission and assist in the evaluation of potential therapeutic treatments.

Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and glial cells

We investigated the effects of neuromelanin (NM) isolated from the human substantia nigra and synthetic dopamine melanin (DAM) on neuronal and glial cell lines and on primary rat mesencephalic cultures. Lactate dehydrogenase (LDH) activity and lipid peroxidation were significantly increased in SK‐N‐SH cells by DAM but not by NM. In contrast, iron‐saturated NM significantly increased LDH activity in SK‐N‐SH cells, compared with 100 mg/mL ETDA‐treated NM containing a low concentration of bound iron. DAM, but not NM, stimulated hydroxyl radical production and increased SK‐N‐SH cell death via apoptotic‐like mechanisms. Neither DAM nor NM induced any changes in the glial cell line U373. 3H‐Dopamine uptake in primary rat mesencephalic cultures was significantly reduced in DAM‐ compared with NM‐treated cultures, accompanied by increased cell death via an apoptosis‐like mechanism. Interestingly, Fenton‐induced cell death was significantly decreased in cultures treated with both Fenton reagent and NM, an effect not seen in cultures treated with Fenton reagent plus DAM. These data are suggestive of a protective role for neuromelanin under conditions of high oxidative load. Our findings provide new evidence for a physiological role for neuromelanin in vivo and highlights the caution with which data based upon model systems should be interpreted.

Monoamine oxidase inhibition and CNS immunodeficiency infection.

HIV invades CNS subcortical areas, particularly the dopamine-rich basal ganglia and induces a subcortical dementia. Data suggest that the basal ganglia dysfunction plays a critical role in the neuropsychiatric manifestation of HIV infection. Therefore, therapeutic approaches for HIV dementia nowadays wish to include apart from the highly active antiretroviral therapy (HAART) also adjunctive medication. In this short article, we report briefly on neurotoxicity associated with the immunodeficiency virus and discuss the effects of selegiline, a monoamine oxidase inhibitor which enhances dopamine availability in CNS on immunodeficiency virus-induced neurological disease.

Brain Iron and other Trace Metals in Neurodegenerative Diseases

Iron is the most abundant metal in the human body and the brain, like the liver, contains a substantially higher concentration of iron than of any other metal (Yehuda and Youdim, 1988). It is an essential participant in many metabolic processes including a) DNA-, RNA- and protein synthesis, b) as a cofactor of many haem and non-haem enzymes, c) the formation of myelin and d) the development of the neuronal dendritic tree (Youdim et al., 1991). Within the brain, iron shows an uneven distribution with high levels in the basal ganglia (substantia nigra, putamen, caudate nucleus, globus pallidus), the red nucleus, and the dentate nucleus (e.g. Riederer et al., 1989). Iron deposition in the brain is mainly in organic storage forms such as ferritin but not haemosiderin (Octave et al., 1983) with relatively little in a free and reactive form. Unlike other tissues, the turnover of brain iron is extremely slow and serum iron has little access to it (Youdim, 1985). All the iron that is present in the brain is deposited before the closure of blood-brain barrier, whereas it is tightly regulated and highly sequestered.

Erratum to: Methylphenidate enhances neural stem cell differentiation

* Correspondence: jasmin.bartl@kjpdzh.ch Hospital of Child and Adolescent Psychiatry, University of Zurich, Winterthurerstr. 180, Room L84/86, 8057, Zurich, Switzerland Full list of author information is available at the end of the article Figure 1 Murine neural stem cell (mNSC) differentiation into immature neurons. A) mNSCs were treated with different concentration (0nM, 1nM, 10nM, 100nM) of methylphenidate (MPH). The percentage (% control) of developed neurons was determined 4 days after treatment with MPH. The amount of immature neurons was analyzed by counting the neuron-specific class III beta-tubulin (Tuj 1) positive cells in comparison to the total number of cells by using the Mann–Whitney (U-Rang) Test; -– = p <0.05; n = 28; seven independent experiments and four wells/slide of each concentration were evaluated. B) An example of an immunocytochemistry staining of Tuj 1 in a control sample (no MPH treatment). The white arrow points to a Tuj 1 positive cell (green) and the white arrow points to a cell nucleus staining with Hoechst (blue); 40x magnification.

Dopamine Is a Pathogenetic Factor in HIV-Induced Neuro-AIDS

During the first years of the AIDS pandemic caused by the human immunodeficiency virus (HIV), a progressive, dementing illness, later called simply Neuro-AIDS, AIDS dementia complex or HIV dementia was defined as one of the consequences of the viral brain infection (Navia et al., 1986a; Navia et al., 1986b). According to WHO report, December 2000, it is estimated that around 36 million people world wide are infected with HIV. One-third of them is expected to develop HIV-dementia. HIV is the leading cause of dementia in people less than 60 years of age (Janssen et al., 1992; McArthur et al., 1993).

Zukünftige und nicht zugelassene Therapien der Parkinson-Krankheit

Wie in den vorhergehenden Kapiteln ausfuhrlich erortert, ist ein Hauptproblem der l-DOPA-Therapie, dass mit zunehmender Behandlungsdauer ein Wirkverlust und gehauft das l -DOPA-Langzeitsyndrom auftreten, dessen Behandlung grose Anforderungen an den behandelnden Arzt stellt und in vielen Fallen medikamentos nur schwer in den Griff zu bekommen ist. Eine schon jetzt mogliche Therapieoption ist die fruhe Monotherapie mit Dopamin-Rezeptoragonisten, NMDARezeptorantagonisten oder Selegilin, die die Notwendigkeit mit l-DOPA zu therapieren hinausschieben. Alternativ konnte man auch l-DOPA einsparen, in dem man die Parkinson-Therapie mit einer Kombination aus l-DOPA-Praparaten und diesen potenziell neuroprotektiven Wirkstoffen beginnt. Noch nicht klinisch untersucht ist die fruhe Kombinationstherapie mit l-DOPA-Praparaten und dem COMT-Hemmer Entacapon.

Hypothesen zur molekularen Pathogenese der Parkinson-Krankheit

Es gibt zwar selten vorkommende familiare Formen des IPS, bei denen zum Teil die Gen-Mutationen und die mutierten Proteine bekannt sind (Tab. 1.2, Kap. 1.3), die grose Mehrzahl der Falle tritt aber sporadisch auf. Man geht davon aus, dass dies etwa 95 Prozent aller Falle des IPS sind. Die Ursache(n) dieses sporadischen IPS ist (sind) bis heute unbekannt. Wahrscheinlich spielen sowohl exogene (z. B. Umwelttoxine) als auch endogene Faktoren (altersabhangige Prozesse, Personlichkeit, genetische Pradisposition, besondere Vulnerabilitat der dopaminergen SN-Neuronen) in jeweils unterschiedlichem Ausmas fur die Entstehung der Erkankung eine Rolle. Die Entdeckung, dass MPTP ein Parkinson-Syndrom beim Menschen verursachen kann, und die Untersuchung der Frage, auf welche Weise MPTP dopaminerge Neuronen schadigt, haben jedoch das Verstandnis des Krankheits-prozesses im allgemeinen erweitert und molekulare Pathomechanismen aufgedeckt, die die Degeneration dopaminerger Neuronen erklaren konnen. Hierzu beigetragen hat aber auch die Erforschung der Wirkungsweise weiterer Neurotoxine (Eisen, 6-OHDA, exzitotoxische Aminosauren) und mutierter Genprodukte (α-Synuclein, Parkin). Diese Erkenntnisse waren die Grundlage fur die Aufstellung verschiedener Hypothesen zur molekularen Pathogenese der Parkinson-Krankheit und zur Entwicklung entsprechender neuroprotektiver Therapieansatze (Tab. 5.1). Auf die neuroprotektiven Thera-pieansatze werden wir ausfuhrlich im nachsten Kapitel eingehen.