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MitoNews
Mitochondrial Research Bulletin
Published by:
MitoSciences
Advancing Vital Discoveries in Mitochondrial Research
http://www.mitosciences.com
Edited by:
Dr. Roderick Capaldi
[email protected]
Volume 03, Number 01 - January, 2007
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html
In this Issue:
1. Role of mitochondria in Parkinson’s disease.
2. Contribution of pink1 to Parkinson’s disease.
3. Animal models that recapitulate the human condition.
4. Drosophila as the animal of choice for Pink1 studies.
5. Loss of function as a result of pink1 inactivation.
6. Pink1 Mutation.
7. Importance of oxidative stress in Parkinson’s disease.
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1. Role of Mitochondria in Parkinson’s disease.
This month’s MitoNews focuses on exciting developments during
2006 on the role of mitochondria in Parkinson’s disease. I feel
comfortable in saying that there is at last an “almost” general
consensus that mitochondrial dysfunction is at the heart of Parkinson’s.
The long standing evidence that environmental toxins
such as rotenone and MPTP induce the disease symptoms through
inhibition of complex I is now added to by strong genetic evidence
of mitochondrial involvement. For useful reviews of PD
published this year the reader is referred to ;
1)ABOU-SLEIMAN, PM., MUQIT,MM & WOOD.NW.
Nat. Rev. Neurosci. 7. 207-219 (2006).
2) HARDY.J, CAI.H, COOKSON.MR, GWINN-HARDY.K & SINGLETON.A.
Ann. Neurol. 60. 389-98 (2006).
3) BURN.DJ, J. Neural. Transm. Suppl 70. 361-5 (2006)
4) SAVITT.JM, DAWSON.VL & DAWSON.TM. J. Clin. Invest. 116. 1744-54 (2006).
2. Contribution of pink1 to Parkinson’s disease.
A major advance in the last year has been in understanding the
contribution of pink1 to PD. It has been known for some time that
this protein is a kinase with mitochondrial proteins as substrate, but
it remains to be determined which of the many phosphorylated
proteins in the organelle are involved, or what is the signaling
pathway for the kinase action.
In a recent paper Ghandi et al describe the ubiquitous expression of
pink1 throughout the brain and provide further strong evidence that
the protein is mitochondrially located. They find the protein in
Lewy bodies both in patients with pink1 mutations, and
importantly, in cases of sporadic PD. It is absent in tangles seen in
patients with Alzheimer’s disease and other forms of brain
neurodegeneration.
5) GHANDI. S. and 13 others.
Pink1 protein in normal human brain and Parkinson’s disease.
Brain. 129. 1720-31 (2006)
3. Animal models that recapitulate the human condition.
An important issue for studies of any disease is to have animal
models that recapitulate the human condition as closely as
possible. This is discussed clearly by Tan and Dawson in recent news and views.
6) TAN.JMM & DAWSON. TM.
Parkin blushed by pink1.
Neuron. 50. 526-8 (2006).
4. Drosophila as the animal of choice for Pink1 studies.
Because of the strong phenotype induced, Drosophila is rapidly
becoming the animal of choice for Pink1 studies, and in 3 studies
using this organism evidence is presented for a strong inter-relation
between pink1 and Parkinson’s.
7) PARK.J, LEE.SB, LEE.S, KIM.Y, SONG.S, KIM.S, BAE.E, KIM.J, SHONG.M, KIM.J-M & CHUNG.J.
Mitochondrial dysfunction in Drosophila Pink1 mutants is complemented by parkin.
Nature. 441. 1157-61 (2006)
8) CLARK. IE, DODSON.MW, JIANG.C, HUH.JR, SEOL.JH, YOO.SI, HAY. BA & GUO.M.
Drosophila pink1 is required for mitochondrial function and
interacts genetically with parkin.
Nature. 441. 1162-66 (2006).
9) YANG.Y and 10 others.
Mitochondrial pathology and muscle and dopaminergic
neuron degeneration caused by inactivation of Drosophila
pink1 is rescued by parkin.
PNAS. 103. 10793-8 (2006)
5. Loss of function as a result of pink1 inactivation.
None of the above papers provide a mechanism for the loss of
function of mitochondria or apoptotic signaling pathways as a
result of pink1 inactivation. The clue may be in two papers, one
by Wang et al. who, again, using Drosophila, inactivate the protein
by RNAi treatment and the other by Hoepken et al.. Wang and
colleagues show that inactivation of pink1 causes progressive loss
of dopaminergic neurons and also ommatidial degeneration of the
eye. Over expression of human superoxide dismutase in these flies
suppresses the neurodegeneration, while SOD and vitamin E
significantly inhibits ommatidial degeneration.
10) WANG.D AND 9 OTHERS.
Antioxidants protect pink1-dependent dopaminergic neurons
in Drosophila.
PNAS . 103. 13520-5 (2006)
6. Pink1 Mutation.
The study of Hoepken et al. uses primary fibroblasts and
immortalized lymphoblasts from 3 patients with a Pink1
mutation. The authors show increased lipid peroxidation and
higher levels of superoxide dismutase and glutathione in these cells
along with decreased complex I activity.
11) HOEPKEN AND 14 0THERS.
Mitochondrial dysfunction, peroxidation damage and
changes in glutathione metabolism in pink1 mutations.
Neurobio. Dis. Nov. 29 (AHEAD OF PRINT)
7. Importance of oxidative stress in Parkinson’s disease.
The importance of oxidative stress in PD was also well
demonstrated by a recent protein chemical study on brain complex
I in PD patients and controls. Briefly, considerably more
oxidative damage was found in the enzyme from PD patients than
in controls with a concomitant loss of one of the subunits of
complex I the 8Kda subunit.
12) KEENEY. PM, XIE.J, CAPALDI.RA & BENNETT.JP.Jr
Parkinson’s disease brain mitochondrial complex I has
oxidatively damaged subunits and is functionally impaired
and misassembled.
J. Neurosci. 26. 5256-64 (2006).
The work of Keeney et. al in which whole brain was analyzed is
one step in demonstrating that the PD related mitochondrial
dysfunction is more broadly distributed than in the substancia
nigra. An important preliminary study indicates the systemic
nature of the mitochondrial effects involved. Thus Shinde and
Pasupathy examined respiratory chain activities in lymphocytes
from patients with PD and in aged matched controls and showed
that these activities, particularly for complex I, were statistically
lower in patients.
13) SHINDE.S & PASUPATHY.K.
Respiratory-chain enzymes in isolated mitochondria from lymphocytes
from patients with Parkinson’s disease: preliminary study.
Neurol. India. 54. 390-3 (2006).
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