This is a very interesting finding in line with our publicaion. We have published already our finding on trace metal increase in moderately affected AD brain compared to control. In particular, we found that Zn was higher than other elements Si, Cu, Mg, Ca, Fe, Al , Fe, etc. However Fe, & Al was extremely elevated only in severe AD. Publiction is available In Alzeimr's Reports Vol 2, No. 4, 1999, pp 241-246. With regards, R.V.Rao & K.S.J.Rao et.al

View all comments by Ranganath Rao

The cloning of the gene for the PARK6 locus by Enza-Maria Valente and her colleagues now gives us a triumvirate of recessive genes that cause parkinsonism in humans; parkin, DJ-1 and now Pink1. Logically, the identification of three recessive mutations with similar phenotypes suggests that either 1) these three genes now delineate a single pathogenic pathway or 2) they point to different pathogenic processes that happen to all cause loss of a small group of neurons in the substantia nigra.

PINK1 looks very much like a serine/threonine-directed protein kinase, and thus has no immediate connection to the E3-ligase activity of parkin or the varied putative activities of DJ-1. This suggests the involvement of diverse cellular pathways. However, there are one or two intersecting observations that may indicate some similarities among these different gene products. The first is that Pink1 localizes to mitochondria. DJ-1 can localize to mitochondria under some circumstances, and a fraction of parkin is also found in this organelle. The proportion of parkin that localizes to...  Read more

The cloning of the gene for the PARK6 locus by Enza-Maria Valente and her colleagues now gives us a triumvirate of recessive genes that cause parkinsonism in humans; parkin, DJ-1 and now Pink1. Logically, the identification of three recessive mutations with similar phenotypes suggests that either 1) these three genes now delineate a single pathogenic pathway or 2) they point to different pathogenic processes that happen to all cause loss of a small group of neurons in the substantia nigra.

PINK1 looks very much like a serine/threonine-directed protein kinase, and thus has no immediate connection to the E3-ligase activity of parkin or the varied putative activities of DJ-1. This suggests the involvement of diverse cellular pathways. However, there are one or two intersecting observations that may indicate some similarities among these different gene products. The first is that Pink1 localizes to mitochondria. DJ-1 can localize to mitochondria under some circumstances, and a fraction of parkin is also found in this organelle. The proportion of parkin that localizes to mitochondria is small, but experiments in mice and flies suggest that there are mitochondrial effects of parkin knockout. The other thing that links these three proteins is that all three protect cells against “stress” in a very broad sense. Thus, parkin protects against proteasome inhibition and mitochondrial stress, DJ-1 against oxidative events (which may be mitochondrial in nature) and proteasome inhibition, and Pink1 protects against proteasomal dysfunction and mitochondrial damage. Which leaves us with a number of important questions to answer. The mechanism by which Pink1 protects cells against mitochondrial damage secondary to proteasome inhibition is unclear and Valente et al. evoke a mitochondrial substrate. So what are the kinase substrates of Pink1? And is Pink1 somehow intertwined with parkin and DJ-1; or is the concept of one pathogenic cascade a red (or pink) herring?

View all comments by Mark Cookson

The two exciting reports in ScienceExpress of two discoveries, one, the mutant Pink1 gene at the root of PARK6-linked autosomal recessive Parkinson disease; and two, the functional inactivation of parkin's ubiquitin ligase activity by S-nitrosylation, provide strong support for an integrated picture of Parkinson's disease. The characterizations of Pink1 localization (and thus, likely, function) in mitochondria and parkin's inactivation as a result of excess oxidative stress cement two cornerstones of PD pathogenesis, mitochondrial impairment and sustained oxidative stress. They also highlight the relevance of wild-type parkin in the development of sporadic, late-onset PD, given its role in regulating steady-state levels of both mitochondrial enzymes and antioxidant proteins in parkin-deficient mouse brain (see Palacino et al., 2004 in ARF related news story).

View all comments by Michael Schlossmacher

Amyloid-β peptides induce DNA fragmentation: an alternative pathway yet to be understood in Alzheimer disease pathology
The paper (Prestwich et al., 2005) has fascinated us and made us believe that we are in the right direction toward exploring an alternative pathway for the pathogenesis of the Alzheimer disease. Our earlier finding of amyloid-β peptides binding to and inducing conformational change in DNA (Hegde et al., 2004) led us to study the effect of amyloid-β peptides on DNA integrity. That other amyloidogenic peptides, such as α-synuclein and prion, also were found to bind to DNA (Veer Bala Gupta et al., 2006), made us argue that there is a common mechanism of action of these peptides at work in neurodegeneration. In this perspective, we highlighted an interesting mechanism of different molecular forms (monomer-oligomer aggregates) of amyloid-β and α-synuclein binding to DNA and inducing DNA damage (Hegde et al., 2004, Abstract). It also gives us insight into understanding the different events taking place at different stages of...  Read more

Amyloid-β peptides induce DNA fragmentation: an alternative pathway yet to be understood in Alzheimer disease pathology
The paper (Prestwich et al., 2005) has fascinated us and made us believe that we are in the right direction toward exploring an alternative pathway for the pathogenesis of the Alzheimer disease. Our earlier finding of amyloid-β peptides binding to and inducing conformational change in DNA (Hegde et al., 2004) led us to study the effect of amyloid-β peptides on DNA integrity. That other amyloidogenic peptides, such as α-synuclein and prion, also were found to bind to DNA (Veer Bala Gupta et al., 2006), made us argue that there is a common mechanism of action of these peptides at work in neurodegeneration. In this perspective, we highlighted an interesting mechanism of different molecular forms (monomer-oligomer aggregates) of amyloid-β and α-synuclein binding to DNA and inducing DNA damage (Hegde et al., 2004, Abstract). It also gives us insight into understanding the different events taking place at different stages of the disease in view of the changing conformation of these peptides in brain.

References:
1. Prestwich EG, Roy MD, Rego J, Kelley SO. Oxidative DNA strand scission induced by peptides. Chem Biol. 2005 Jun;12(6):695-701. Abstract

2. Hegde ML, Anitha S, Latha KS, Mustak MS, Stein R, Ravid R, Rao KS. First evidence for helical transitions in supercoiled DNA by amyloid Beta Peptide (1-42) and aluminum: a new insight in understanding Alzheimer's disease. J Mol Neurosci. 2004;22(1-2):19-31. Abstract

3. Veer Bala Gupta, Hegde ML, Jagannatha K.S The role of protein conformational dynamics and DNA integrity in neuronal Cell death in neurodegeneration. Curr. Alz. Res., 3 (4), (2006) in press.

4. M.L.Hegde, S.Anitha and Jagannatha K.S (2004) Are Monomer-Oligomer Aggregates of Amyloidogenic Peptides Toxic Species in Neurodegeneration, NeuroBiol Aging (Abstract) P1-261, 25, S2, 170.

View all comments by Veer Bala Gupta
View all comments by K.S. Jagannatha Rao

I partially agree with the suggestion that villagers in India who consume mustard oil didn't have AD in old age, also because it was found in current research that turmeric and mustard oil users are less susceptible to AD, but I disagree with his query that we can't relate AD with age as we have certain data for its proof. Age is the most important known risk factor for AD. The number of people with the disease doubles every 5 years beyond age 65. Middle-aged women are at greater risk than men (AD). A recent study shows that high blood pressure dramatically increases this risk, foretelling a potential epidemic of dementia as baby boomers enter their later years. Research at Boston University School of Medicine tracked 4,883 people under evaluation for the Framingham Heart Study. Forty years' worth of data revealed that one in four suffers from AD. Men of the same age are slightly less susceptible, having a one in six chance of AD. Combined, these risk factors threaten one out of every two older women and one in three of their male peers.

I agree with Mr. Ranganath Rao that...  Read more

I partially agree with the suggestion that villagers in India who consume mustard oil didn't have AD in old age, also because it was found in current research that turmeric and mustard oil users are less susceptible to AD, but I disagree with his query that we can't relate AD with age as we have certain data for its proof. Age is the most important known risk factor for AD. The number of people with the disease doubles every 5 years beyond age 65. Middle-aged women are at greater risk than men (AD). A recent study shows that high blood pressure dramatically increases this risk, foretelling a potential epidemic of dementia as baby boomers enter their later years. Research at Boston University School of Medicine tracked 4,883 people under evaluation for the Framingham Heart Study. Forty years' worth of data revealed that one in four suffers from AD. Men of the same age are slightly less susceptible, having a one in six chance of AD. Combined, these risk factors threaten one out of every two older women and one in three of their male peers.

I agree with Mr. Ranganath Rao that trace metals increase risk of AD, as we have with us certain data for lead-related risk of AD. Exposure to lead increases the risk for developing AD, according to a study done at Case Western University Medical School's department of neurology. Individuals in work environments with high levels of lead are three to four times as likely to have Alzheimer's as their unexposed peers later in life. The study offers the first conclusive evidence of a link between on-the-job hazards and AD. Scientists at Case Western examined the work histories of Alzheimer patients and compared them to the histories of healthy elderly people. Dr. Elisabeth Koss and her colleagues discovered that individuals with the highest levels of lead exposure were up to four times as likely to have Alzheimer's as those who had minimal work-related exposure. The research team reported their findings at the 52nd Annual Meeting of the American Academy of Neurology. Even after taking into account a number of other factors that can influence the development of the disease, results showed that 14 percent of Alzheimer patients had experienced lead exposure at work, as compared to just 6 percent of individuals without the disorder. However, no association was made between exposure to other common workplace toxins—such as aluminum, copper, iron, zinc, and solvents—and an increased risk for developing the disease. Typically, lead exposure occurs either by inhaling lead dust (the most toxic mode of transmission) or by absorbing lead through the skin. Jobs that involve smelting and casting lead, working with lead-based paints or inks, making stained glass, or manufacturing products including batteries, lead-glazed pottery, ammunition, lead pipes, and electronics parts place workers at serious risk for high lead exposure. At-home risks also exist where lead is contained in drinking water and soil, or in older homes that have peeling lead-based paint.

References:
1. Ito T, Yamadera H, Ito R, Endo S. [Effects of bright light on cognitive disturbances in Alzheimer-type dementia] Nippon Ika Daigaku Zasshi. 1999 Aug;66(4):229-38. Abstract

2. D. F. Swabb and E. Flievs., Brain Res. 1985;140:566.

3. Brusco LI, Marquez M, Cardinali DP. Monozygotic twins with Alzheimer's disease treated with melatonin: Case report. J Pineal Res. 1998 Dec;25(4):260-3. Abstract

4. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982 Jun;140:566-72. Abstract

5. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. Abstract

6. Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A. Sundowning and circadian rhythms in Alzheimer's disease. Am J Psychiatry. 2001 May;158(5):704-11. Abstract

7. D. L. Bilewis and M. Hughes., J. Gerontol. A. Biol Sci. Med. Sci. 1995;50:303.

View all comments by sumit gupta