Neurology -- Correspondence for Lang, 68 (12) 948-952

Correspondence published:

The progression of Parkinson disease: A hypothesis: William J. Burke (19 April 2007)

Reply from the Author: Anthony Lang (19 April 2007)

The progression of Parkinson disease: A hypothesis 19 April 2007

William J. Burke,
Saint Louis University
3635 Vista at Grand. St. Louis MO 63110
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Re: The progression of Parkinson disease: A hypothesis

burkewj{at}slu.edu William J. Burke

Lang’s Medical Hypothesis article on progression of Parkinson’s disease (PD) [1] inverts the Braak hypothesis. [2] Lang notes that Braak based his hypothesis on Lewy bodies (LB) in brainstem neurons and not on neuronal counts. Lang also suggests that loss of non dopamine (DA) neurons occurs after loss of substantia nigra (SN) DA neurons and not before. He predicts that non motor symptoms (e.g. depression, sleep and autonomic disturbances) due to loss of non DA neurons will persist after a neuroprotective treatment for DA neurons. Consequently, Lang suggests the need for a complex therapeutic cocktail to address basic neurodegenerative mechanisms in DA and non DA neurons alike. However, almost all non DA neuron loss in PD occurs in catecholamine (CA) neurons such as norepinephrine (NE) neurons in locus ceruleus and dorsal motor nucleus of the vagus, epinephrine (Epi) neurons in the rostral ventral lateral medulla and in serotonin (5HT) neurons in the dorsal raphe. [3] Loss of these non DA aminergic neurons can explain most of the major non motor symptoms in PD.
In addition, Blashko predicted that aldehyde MAO metabolites would be highly reactive and toxic to cells in which they are formed. [4] We confirmed Blashko’s hypothesis showing that the MAO metabolites of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and of NE or Epi, 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), are toxic at physiological levels in vitro and in vivo. [3] Both DOPAL and DOPEGAL form free radicals which activate the mitochondrial permeability transition pore leading to cell death. [3] In addition, DOPAL like other free radicals triggers aggregation of alpha-synuclein (AS) to form toxic oligomers and large LB-like(AS) aggregates. [3,5] Therefore these amine- derived aldehydes and their interaction with AS provide a simple explanation for PD pathology including selective amine (DA, NE, Epi, 5HT) neuron loss and large LB-like AS aggregates in the remaining neurons.
The difference in severity and progression of motor vs non motor symptoms in PD could be due to differences in toxicity of the specific amine-derived aldehyde as well as to differences in neuroprotective factors in subsets of aminergic neurons. For instance, we showed that DOPAL is more toxic to DA SN neurons than to DA ventral tegmental area neurons. [3]
Because PD selectively affects aminergic neurons which produce MAO aldehyde metabolites which have similar mechanisms of toxicity [3] there may be simpler neuroprotective treatment strategies,than Lang suggests [1] for most of the disabling motor and non motor PD symptoms.
References
1. Lang AE. The progression of Parkinson’s disease. Neurology 2007; 68: 948-952.
2. Braak H, Del Tredici K, Rib U, De Vos RAI, Steur ENHJ, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24: 197-211.
3. Burke WJ, Li SW, Kumar VB, Kristal BS, Johnson EM, Ruggiero DA. Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. NeuroToxicology 2004; 25: 101-115.
4. Blashko H. Amine oxidase and amine metabolism. Pharmacol Rev 1952; 4: 415-453.
5. Burke WJ, Kumar VB, Pan Y, Panneton WM, Pandey N, Galvin JE. DOPAL, the toxic dopamine metabolite, triggers alpha-synuclein aggregation in vivo. Neurology 2006; 65A.
Disclosure: The author reports no conflicts of interest.

Reply from the Author 19 April 2007

Anthony Lang,
University of Toronto
399 Bathurst St, Toronto, ON, Canada, M5T 2S8
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Re: Reply from the Author

lang{at}uhnres.utoronto.ca Anthony Lang

I thank Dr. Burke for his interest in my hypothesis article. My main proposal is that nigral dopaminergic cell loss may be accelerated for various reasons which could include the mechanisms outlined in his letter. His work is not incompatible with my hypothesis and may correspond to it by adding similar but less pronounced “accelerated” degeneration in other catecholaminergic neurons. Just as the VTA may be less sensitive than SNc neurons to these factors -- as Dr. Burke points out --so may NE, Epi and 5HT neurons (still allowing for a greater acceleration of the degenerative process of the nigra).
However, I did not suggest “that loss of non-dopamine neurons occurs after loss of substantia nigra dopamine neurons not before”. It is also important to point out that, in contrast to Dr. Burke’s claims, many regions of the CNS degenerate in PD and a number of these cannot be explained by a common catecholamine phenotype. As I outlined, there are many potential explanations for the non-dopaminergic, non-motor symptoms of PD. Unfortunately, there is no clear clinical-pathological understanding of these and although some may be explained by the loss of non-DA catecholaminergic neurons, many may not.
I am uncertain of the basis of Dr. Burke’s strong statement that “Loss of these non-DA aminergic neurons can explain most of the major nonmotor symptoms in PD”. One critical example of this is dementia which may be partially explained by involvement of areas such as the cholinergic nucleus basalis of Meynert, hippocampus and other regions of the cortex (Table 1). [1]
It would be reasonable to add to my discussion the possibility of neuroprotective treatment designed to address MAO aldehyde metabolites which, if Burke’s hypothesis is correct, could theoretically influence dopaminergic and non-dopamine aminergic cell loss. However, this may still be inadequate to prevent progressive disability caused by the degenerative process involving other non-aminergic regions. Therefore, as proposed in my paper, the “cocktail” neuroprotective approach may still be required depending on when in the disease process treatment is initiated.
Disclosure: The author reports no conflicts of interest.