Lewy bodies are found in cells that don't produce dopamine.

See: Lewy body dementia.

can you expand on this for the less scientific (or intuitive) amongst us (i.e. me).

Thank you,
Neil.

Parkinson's probably does not start in the brain, or even in dopamine neurons. Whatever kicks it off happens in other places like the gut, the spine, or other less central locations. The presence of alpha synuclein aggregates as neurite filaments and Lewy bodies in places like the vagus nerve, for instance, years before their appearence in the basal ganglia convinces me of this.

My money is on an inflammatory trigger that activates macrophages/microglial cells of the endogenous immune system to produce superoxide and other ROSs (reactive oxygen species). It is likely to initially be an over-reaction of an otherwise normal immune response to some substances that are mistaken for a foreign invader; something like what Heidi is referring to in gluten sensitivity, but not always involving the formation of antibodies by the adaptive immune system.

Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies. A classical Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core surrounded by a halo of 10-nm wide radiating fibrils, the primary structural component of which is alpha-synuclein. In contrast, a cortical Lewy body is less well-defined and lacks the halo. Nonetheless, it is still made up of alpha-synuclein fibrils.
(wikipedia)

Lewy bodies have been found in a diverity of locations including monoaminergeic and cholinergic neurons of the brainstem, diencephalon, basal forebrain, cerebral cortex, and autonomic ganglia.
Dementia with Lewy Bodies: Clinical, Pathological, and Treatment Issues By Robert Perry, Ian G. McKeith, Elaine K. Perry. p 288

Enteric malfunction in PD: It was Braak et al. who showed that the first morphological abnormalities such as Lewy bodies and alpha-synuclein deposition do not occur in the substantia nigra, but in the olfactory bulb and in the vagal and glossopharyngeal nuclei. (Braak et al. 2003). The same authors claim that even before this the first Lewy bodies (LB) or a-synuclein inclusions may be found in the enteric nervous system, i.e. gastric, myenteric and submucosal plexuses (also known as Auerbach and Meissner Plexus) (Braak et al. 2005).


(I actually got out a book and typed some of this in. Been a while!)

"Oxidation of dopamine by monoamine oxidase results in the endogenous metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). "

Rasagiline (Azilect): A second-generation monoamine oxidase type-B inhibitor

Hmmmmmmm......

DOPAL may cause dysfunction in the mitochondria:

DOPAL (3,4-dihydroxyphenylacetaldehyde), a monoamine oxidase metabolite of dopamine,
also has been shown to be a potent inducer of the mPT.......

The mitochondrial permeability transition in neurologic disease

Neurochemistry International
Volume 50, Issues 7-8, June 2007,

Abstract

Mitochondria, being the principal source of cellular energy, are vital for cell life. Yet, ironically, they are also major mediators of cell death, either by necrosis or apoptosis. One means by which these adverse effects occur is through the mitochondrial permeability transition

(mPT) whereby the inner mitochondrial membrane suddenly becomes excessively permeable to ions and other solutes, resulting in a collapse of the inner membrane potential, ultimately leading to energy failure and cell necrosis. The mPT may also bring about the release of various factors known to cause apoptotic cell death.

The principal factors leading to the mPT are elevated levels of intracellular Ca2+ and oxidative stress. Characteristically, the mPT is inhibited by cyclosporin A. This article will briefly discuss the concept of the mPT, its molecular composition, its inducers and regulators, agents that influence its activity and describe the consequences of its induction.

Lastly, we will review its potential contribution to acute neurological disorders, including ischemia, trauma, and toxic-metabolic conditions, as well as its role in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

3,4-Dihydroxyphenylacetaldehyde: A Potential Target for Neuroprotective Therapy in Parkinson's Disease

CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders), Volume 2, Number 2, April 2003

Abstract:

The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD:

1. Hereditary PD contains mutations in the gene for agr-synuclein (agr-syn). Investigations implicate a DA metabolite as mediator of agr-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo.

2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo.

3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL.

4. Free hydroxyl radicals (.OH) trigger aggregation of agr-syn to its toxic form. DOPAL with H2O2 generates .OH radicals.

These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA.

2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors.

3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity.

4. Coenzyme Q10 increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor.

5. DA uptake blockers could be used to limit intraneuronal DOPAL production.

6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD.

7. Agents which block aggregation of agr-syn should limit DOPAL toxicity.

On the other hand....

Semi-chronic increase in striatal level of 3,4-dihydroxyphenylacetaldehyde does not result in alteration of nigrostriatal dopaminergic neurones

Hélène Legros, François Janin

Journal of Neuroscience Research

RSS feed for Journal of Neuroscience Research What is RSS?
Volume 75, Issue 3 , Pages 429 - 435

Published Online: 6 Jan 2004

Abstract
This work was carried out to evaluate the potential in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL), an aldehyde formed from dopamine by monoamine oxidase (MAO) that is oxidised mainly to 3,4-dihydroxyphenylacetic acid (DOPAC) by brain aldehyde dehydrogenases (ALDH). In this study, male Sprague-Dawley rats were treated with levodopa (L-dopa)-benserazide, which increases DOPAL production by MAO, and disulfiram, an irreversible inhibitor of ALDH, which reduces the formation of DOPAC from DOPAL. An acute systemic intraperitoneal (i.p.) injection of 100 mg/kg disulfiram and L-dopa-benserazide (100 mg/kg + 25 mg/kg, 24 hr later) significantly increased DOPAL striatal level. A 30-day treatment with disulfiram (100 mg/kg i.p., once every 2 days) and L-dopa-benserazide (100 mg/kg + 25 mg/kg, two times/day) did not affect either indexes used to assess integrity of the nigrostriatal dopaminergic neurones (i.e., the striatal content in dopamine and binding to the vesicular monoamine transporter on striatal membranes). These results do not evidence any deleterious effect of DOPAL and argue against toxicity of L-dopa therapy. © 2004

http://www3.interscience.wiley.com/c...9617/HTMLSTART

I don't know about all the chemistry sited in the above postings, my warped little brain doesn't work that way anymore. The thing I do find interesting though are the dates of the reports listed in the postings. This information has been around since at least 2001.
This is another indication that the Parkinson community is not communicating it's findings with each other. They all want to be the ONE that discovers the cure. Go figure!

Greg

So it is back to Michael J. Fox's question,"Who's in Charge of Finding Cures?"

Vicky